Identification of two novel susceptibility variants on chromosome 5p15.33 for non-small cell lung cancer in Chinese population

Identification of two novel susceptibility variants on chromosome 5p15.33 for non-small cell lung cancer in Chinese population | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Identification of two novel susceptibility variants on chromosome 5p15.33 for non-small cell lung cancer in Chinese population Zhi Ji, Ying Li, Cheng Xiang, Xia Luo, Peihong Yuan, Jieyi Long, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.11710/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Abstract Background：Genome-wide association studies (GWAS) have identified 5p15.33 as a susceptibility locus for lung cancer. However, for non-small cell lung cancer (NSCLC), low-frequency risk variants in this region have not been systematically identified and studied. We have screened low-frequency variants on chromosome 5p15.33 in Chinese NSCLC patients by targeted sequencing before. Methods：In this study, we selected candidate variants from low-frequency variants by comparing the genotype frequency of 400 NSCLC patients with 1,008 East Asians from The genome Aggregation Database (gnomAD). The associations between candidate variants and NSCLC were then discovered and replicated in two case-control sets: stage I with 960 cases and 916 controls, and stage II with 1,596 cases and 1,614 controls in total. Results：Among the 5 candidates, 2 polymorphisms were significantly associated with risk of NSCLC, including rs33963617 (OR = 0.63, 95% CI: 0.53-0.76, P = 3.80 × 10-7) in TERT and rs77518573 (OR = 0.73, 95% CI: 0.63-0.84, P = 2.00 × 10-5) in CLPTM1L. When stratified by histologic subtype, a significant association was only investigated in adenocarcinoma for rs77518573. We also observed an obvious cumulative effect of the two significant variants. Conclusions: We newly identified two NSCLC related variants on chromosome 5p15.33. Both TERT-rs33963617 and CLPTM1L-rs77518573 conferred reduced risk for NSCLC in Chinese population. Our study gives new insight into the power of low-frequency variants in explaining cancer heritability and expands our understanding about the essential role of TERT-CLPTM1L region in lung cancer development. Keywords: non-small cell lung cancer, 5p15.33, low frequency, genetic variant, susceptibility Cancer Biology non-small cell lung cancer 5p15.33 low frequency genetic variant susceptibility Figures Figure 1 Background Lung cancer is the most common diagnosed malignancy around the world.[1] In China, the morbidity and mortality of lung cancer ranks the first among various malignancies, with an estimated 733,300 new cases and 610,200 deaths in 2015.[2] Environmental factors such as unhealthy lifestyle, fine-particulate air pollution and occupational exposure play the primary role in causing sporadic lung cancer.[3-5] Epidemiological investigations have showed that about one fifth lung cancers were attributable to cigarette smoking.[6] However, only a small proportion of the smokers would be suffered from lung cancer during whole lifetime, suggesting that genetic background might be a noticeable reason influencing the individual susceptibility to this disease.[7] In recent years, genome-wide association studies (GWAS) have revealed amounts of gene loci predisposing for multiple malignancies in different populations. Chromosome 5p15.33 has been reported as a pleiotropic locus which associated with a variety of tumors such as lung cancer, glioma, breast cancer, ovarian cancer, and pancreatic cancer.[8-11] The discovery of the lung cancer susceptibility variants such as rs2736100 and rs401681 indicated this region might play an important role in lung cancer development.[12, 13] There are two plausible genes in chromosome 5p15.33, namely, the telomerase reverse transcriptase ( TERT ) gene and the cleft and palate transmembrane1 like ( CLPTM1L ) gene. The gene TERT encodes a catalytic subunit of telomerase reverse transcriptase which participated in maintaining the stability of chromosomes and ensuring the integrity of genetic information.[14] Telomerase was usually suppressed and inactive in most of the matured somatic cells, while about 85% of tumor cells could detect telomerase activity in varying degrees, suggesting a crucial role of TERT in emergence of tumors.[15, 16] CLPTM1L encodes a highly conserved transmembrane protein which was implicated in cell apoptosis and over-expressed in lung cancer tissues.[17, 18] Although systematic fine-mapping has been conducted to prioritize and characterize the causal variants in this region, the underling carcinogenic mechanisms have not been fully understood until now.[19, 20] In our previous study, we performed a targeted sequencing based approach on TERT-CLPTM1L region to identify NSCLC associated common (minor allele frequency (MAF) ≥ 5.0%) variants and found that single nucleotide polymorphism (SNP) rs7726159 conferred lung cancer risk might by affecting MYC binding and inducing telomere lengthening.[21] However, evidences suggested that in addition to common variants, polymorphisms with low-frequency can also contribute to cancer susceptibility.[22, 23] To uncover the NSCLC related low frequency variants, we systematically assessed the association of low-frequency genetic variants in TERT-CLPTM1L region with the risk of NSCLC in a Chinese population in this study. Candidate variants were selected by comparing the frequency of low-frequency variants in 400 NSCLC patients scanned by previous targeted sequencing with that of East Asians (EAS) from The genome Aggregation Database (gnomAD). The relationships between candidate variants and NSCLC were further estimated by conducting a two-stage case-control study with a total of 2,556 NSCLC patients and 2,530 healthy controls. Methods 2.1. Study subjects As mentioned before, we enrolled 400 newly diagnosed NSCLC patients for targeted sequencing and acquired the spectrum of variation on chromosome 5p15.33.[21] In this study, we recruited a total of 2,556 patients with NSCLC and 2,530 healthy controls, partly contained in our previous study, to discover and validate the population associations. Patients were enrolled continuously from the Tongji Hospital of Huazhong University of Science and Technology (HUST), Wuhan, China during Jan 2014 to Jan 2018. Primary NSCLC cases with histological or cytological confirmation were eligible, while patients with previous cancer history, metastatic NSCLC from other organs, and previous treatment with radiotherapy or chemotherapy were excluded. Healthy controls with no history of malignant tumors and major diseases were randomly selected from subjects who went to the check-up center at the same hospital during the same time as the cases recruited. All the controls were frequency matched to the cases by age and gender. Three milliliter peripheral venous blood of all participants were collected in tubes with EDTA anticoagulant and stored freezingly at -80℃. All the participants received written informed consent and interviewed face-to-face on a standard questionnaire about basic demographic characteristics. This study was approved by the Institutional Review Committee of the Tongji Hospital, Tongji Medical College, HUST. 1.2. Selection of the candidate SNPs Based on the results of targeted sequencing in our previous research,[21] we captured a total of 1,478 variants on chromosome 5p15.33 in 400 NSCLC patients. One thousand two hundred and fifteen variants were removed according to their rare frequency (MAF＜1.0%). Among the remaining SNPs, 237 variants got through the quality control and 31 of them were defined as low-frequency variants with MAFs range from 1% to 5%. We thus downloaded the genotype frequency data of these 31 variants in 1,008 East Asians from gnomAD and compared each variant with frequency of our NSCLC patients. Significant variants in comparisons were selected as candidates. 1.3. DNA extraction and genotyping The RelaxGene Blood DNA system DP349-02 (TIANGEN, Beijing, China) was used to extract genomic DNA from peripheral blood. The candidate SNPs were genotyped using the TaqMan SNP genotyping analysis on the ABI ViiA TM 7 Real-Time PCR System (Applied Biosystems, Foster City, CA, USA). All assays were performed on 384-well plates with mixed cases and controls. Positive and negative samples were used for quality control on each plate. Ten percent samples were randomly selected for repetition, and the coincidence rate reached 98%. 1.4. Statistical analyses Unpaired student’s t-test was utilized to compare the distribution of continuous variable (age) between cases and controls. And Pearson’s χ-square test was used to evaluate the difference of categorical variables about demographic characteristics (gender and smoking status) as well as genotypes in two groups. Hardy-Weinberg equilibrium (HWE) was calculated for each variant by using goodness-of-fit χ-square test among controls. Unconditional multivariate logistic regression was used to evaluate the effect of candidate variants on NSCLC susceptibility in total and subgroups analysis. All statistical analyses were performed in SPSS 21.0, and two-sided P value less than 0.05 was considered statistically significant. Results 3.1. Characteristics of the study subjects The demographic characteristics of all subjects and the basic clinical features about the NSCLC patients are shown in Table 1. A total of 2,556 NSCLC cases and 2,530 healthy controls were included in this study. In discovery stage with 960 cases and 916 controls, 69.4% of the patients diagnosed with NSCLC were males, and in healthy controls, males occupied a percentage of 68.1%. The mean (SD) age of the case and control groups were 58.0 (9.8) years and 58.6 (9.5) years, respectively. In the replication stage, we enrolled 1,596 NSCLC cases and 1,614 healthy controls. The mean (SD) age was 54.5 (7.4) in cases and 54.8 (7.6) in controls. Males accounted for 64.7% among cases compared with 65.8% among controls. When combining the two stages, there were no significant differences in distribution of gender (66.5% males in cases, 66.6% males in controls, P = 0.898) and age (55.8±8.5 years for cases, 56.2±8.6 years for controls, P = 0.087) between two groups. It's worth noting that more smokers were observed in NSCLC patients than healthy controls in both the two stages ( P values being 0.006 for discovery stage and 3.07×10 -4 for replication stage) as well as the combined samples ( P = 0.002). Besides, more than 60% of the tumors were confirmed as adenocarcinomas and about 30% were squamous cell carcinomas (SCC), while the remaining cancers were other non-small cell histological types. Based on the Lung Cancer TNM classification criteria (IASLC 2009), 35.5% of the total NSCLC patients were diagnosed in an early stage (0, I or II stages) and 58.9% cases were in late stage (III and IV stages). 1.5. Screening of the candidate variants Among the 31 low-frequency variants identified by sequencing in our NSCLC patients, seven variants were statistically significant when comparing their frequency with that of the East Asians from gnomAD (Supplementary Table 1). We therefore selected these seven SNPs as our candidate variants. However, two of the candidates which located in segmentally duplicated regions were failed in prob design, thus the remaining 5 polymorphisms were successfully genotyped and further analyzed. 1.6. Association between candidate SNPs and NSCLC susceptibility In the discovery stage, we assessed the associations between 5 candidate variants and NSCLC susceptibility in 960 cases and 916 controls. As shown in Table 2, two polymorphisms were significantly associated with NSCLC risk, including rs33963617 (OR = 0.71, 95%CI: 0.53-0.94, P = 0.018 in dominant model) and rs77518573 (OR = 0.68, 95%CI: 0.53-0.88, P = 0.003 in dominant model). No significant association was observed between the other three variants and risk of NSCLC in this population. Based on these findings, we further validated the two promising associations in a replicated case-control study with a total of 1,596 cases and 1,614 controls. As a result, the two SNPs exhibited consistent significant relationships with NSCLC, with the estimated ORs being 0.59 (95%CI: 0.47-0.74, P = 4.00×10 -6 ) for rs33963617 and 0.75 (95%CI: 0.63-0.90, P = 0.002) for rs77518573 under a dominant model. The associations retained significant when combining the samples of the two stages together (Table 3). People carrying the rs33963617 AG or AA genotypes had a reduced risk for NSCLC comparing with subjects harboring the GG homozygotes (OR = 0.63, 95% CI: 0.53-0.76, P = 3.80×10 -7 ). As for rs77518573, a protective effect towards NSCLC was also observed in subjects carrying the minor allele: comparing with the wild CC genotype, the variant genotypes (AC or AA) conferred a significant decline in NSCLC risk (OR = 0.73, 95%CI: 0.630-0.84, P = 2.00×10 -5 ). However, the impact of the mutant homozygotes seemed non-significant for both two variants owing to their scarcity in population. Since the two significant variants, rs33963617 and rs77518573, were adjacent with a physical distance of about 67 kb on chromosome location, we next examined whether these variants have cumulative association by counting the number of associated alleles in each subject. Individuals carrying more than one minor allele conferred significant reduced risk than those carrying no minor allele at the two variants, and there was a gradual decrease in OR with a greater number of minor alleles (Figure 1). Specifically, compared with individuals carrying no minor allele, individuals carrying one, two or more minor alleles had an adjusted OR of 0.75 (95% CI: 0.66-0.85, P = 1.10×10 -5 ) and 0.34 (95% CI: 0.23-0.49, P = 1.06×10 -8 ), respectively. Stratification was primarily implemented by smoking status according to the deleterious influence of smoking on lung cancer (Table 4). Among non-smokers, both the variants showed protective effects against NSCLC, with the adjusted ORs being 0.65 (95%CI: 0.51-0.83, P = 0.001) for rs33963617 and 0.68 (95%CI: 0.56-0.83, P = 1.82×10 -4 ) for rs77518573. Smokers with the variant genotypes of rs33963617 exhibited significant reduced risk of NSCLC compared with smokers harboring the wild-type genotype (OR = 0.69, 95% CI: 0.54-0.89, P = 0.005 ). While for rs77518573, we observed a marginal effect in smokers, with OR of 0.82 (95%CI: 0.67-1.02, P = 0.075). However, no prominent interaction was found between smoking and rs77518573 ( P = 0.404) or rs33963617 ( P = 0.853). When stratified the NSCLC patients by pathological type, we found remarkable and consistent associations for rs33963617 with both adenocarcinoma (OR = 0.66, 95%CI: 0.56-0.79, P = 2.00×10 -6 ) and SCC (OR = 0.68, 95%CI: 0.52-0.90, P = 0.007) (Table 4). The SNP rs77518573 was confirmed significantly associated with only adenocarcinoma (OR = 0.60, 95%CI: 0.49-0.74, P = 1.00×10 -6 ) but not SCC (OR = 0.85, 95%CI: 0.67-1.06, P = 0.148). Discussion Growing evidence showed that common variants in the TERT-CLPTM1L region account for the bulk of malignancies including NSCLC, while comprehensive investigation is limited about disease-related low-frequency variants in this region. In current study, a targeted-sequencing based approach was performed to identify low frequency variants contributing to NSCLC. Genotyping in two stage case-control studies revealed that two genetic variants, rs33963617 and rs77518573 were significantly associated with NSCLC in Chinese population. Moreover, a significant cumulative effect with the risk of NSCLC reducing was illustrated as the number of variant genotypes increased. During the past decade, GWASs have demonstrated dozens of genetic loci which predisposing to lung cancer. However, the known common variants identified by GWASs are collectively responsible for less than 30% of lung cancer heritability, indicating much of the genetic architecture to lung cancer remains unexplained.[24] Except for common variants, low frequency variants have been proposed as a portion source of heritability and therefore may be associated with the risk of complex diseases.[25, 26]Exome-wide scan and sequencing based approaches are commonly used strategies to assess the relationship of low-frequency and rare variants with cancer or other complex traits.[27, 28] To date, several low-frequency variants have been uncovered to be associated with lung cancer susceptibility and even prognosis.[29, 30] Fine-mapping based on deep sequencing of the chromosome 5p15.33 has been conducted to define the causal lung cancer susceptibility loci.[19, 20, 31] However, little attention has been drawn to the characterization of the disease associated low-frequency variants in this region. Our study provides compelling evidence that low-frequency variants within TERT-CLPTM1L , a well known GWAS locus on chromosome 5p15.33, can modulate risk of NSCLC in a Chinese population. These findings support an important role of low-frequency variants in lung cancer development and shed light on their capacity in explicating the missing heritability of complex traits. The beneficial effects of rs33963617 and rs77518573 against lung cancer were confirmed for the first time in this study. SNP rs33963617 (c.2097G>A, p.Ala699=) is a synonymous variant located in the 5 th exon of TERT gene. In particular, it is a low-frequency (MAF: 4.9%) variant in our NSCLC patients while commonly (MAF: 7.4%) arised in healthy controls. According to data from dbSNP, the frequency of this variant is much higher in East Asians (8.0%) than the other ethnic populations such as Europeans (0.7%), Africans (0.2%) and Americans (0.3%).[32]Therefore, the prominent association between rs33963617 and NSCLC risk may be specific in Chinese population considering the allelic discrepancy among different populations. Although no significant association with cancer has been reported previously, we found that rs33963617 was recorded in ClinVar database and annotated in relation to an inheritable disease called dyskeratosis congenital.[33] Intriguingly, dyskeratosis congenital is referred to as a telomere biology disorder accompanied with aberrant telomerase activity and telomeric imbalance which were generally driven by mutations linked to telomere maintenance.[34, 35] Telomere dysfunction can trigger cellular senescence and constitute a driving force for tumorgenesis by inducing limitless replicative potential and causing extensive genome instability, both of which were the hallmarks of cancer.[36, 37] Without changing the amino acid sequence, synonymous variant can also mediate gene regulation via transcriptional or post-transcriptional manner.[38-40] Hence, we speculate that rs33963617 may play a part in telomere biology and thus contribute to lung cancer susceptibility. However, further in vivo and in vitro experiments are required to arbitrate the concrete function of this variant and elucidate the potential mechanisms in tumorigenesis. CLPTM1L is the other candidate gene at chromosome 5p15.33, albeit not as famous as TERT . The expression of this gene has been found increased in lung adenocarcinomas compared to matched normal lung tissues.[20] Meanwhile, over-expression of CLPTM1L predicted a poor survival of lung cancer patients.[41] Functional characterization established a protumorigenic role of CLPTM1L for Ras-driven lung cancer due to its regulation on cell survival signaling.[42] Several SNPs in the CLPTM1L gene have been reported to be associated with decreased risk of lung cancer.[43] And the risk genotype at this locus rendered a cis-regulation on CLPTM1L expression, suggesting a conceivable causative role of CLPTM1L in cancer development.[42] In our study, we newly identified a protective effect of non-coding variant rs77518573 against NSCLC. Notably, the frequency of rs77518573 was also disparate among different populations (9.4% in East Asians, less than 1% in Africans and Europeans and absent in Americans), insinuating a particular relationship with NSCLC in Chinese population. Since situates merely 1.6 kb upstream the transcription start site (TSS) of the CLPTM1L gene, the SNP rs77518573 is supposed to be a potential regulatory variant residing in a traditional promoter element.[44] Promoter is an essential component for transcription initiation and the assembly of RNA polymerase and associated regulators. Variants in this element thus may modulate the expression of its target gene by affecting the binding of transcriptional activators or repressors. Nevertheless, whether the SNP rs77518573 mediates a regulation to CLPTM1L and the underlie mechanisms need further elaboration in future. We detected an obvious cumulative effect between the significant variants TERT -rs33963617 and CLPTM1L - rs77518573 . This finding highlights the importance of both the TERT and CLPTM1L genes in lung cancer occurrence and prompts an additive or synergetic effect for non-linkaged variants in the same locus. In subgroup analysis, we observed consistent conspicuous associations with adenocarcinoma and SCC for TERT -rs33963617, while only significant relation to adenocarcinoma for CLPTM1L -rs77518573. Coincidentally, a previous study investigated similar results which showing concurrent associations with different histologic types of NSCLC for a common variant in TERT , whereas just significant correlation with SCC for another variant in CLPTM1L .[45] More than corroborate the pathological heterogeneity of lung cancers, the disparity may also remind the distinct carcinogenic mechanisms of the two genes. Our study comprehensively investigated the relationship between low-frequency variants on chr5p15.33 and NSCLC susceptibility in Chinese population. Based on two stage case-control study representing a total of more than 5,000 subjects, we identified two novel NSCLC risk associated variants. Owing to the relative high variation frequency in East Asians and divergent genetic background among different populations, the significant associations with NSCLC may be specific in Chinese population. While considering the lack of the two protective alleles in races beyond yellow, people in west countries may be confronted with an elevated hazard for NSCLC by nature comparing with the people in East Asian. However, limitations should be addressed. Firstly, we scanned potential low-frequency variants in only 400 NSCLC patients which may lead to frequency departure. In fact, the significant variants were proved to be common in healthy controls though their frequency were much lower, even rare or absent, in other ethnicities. Replication of the associations may be thus required in other ethnic populations. Second, despite the prominent cumulative effect of the two significant variants, we didn’t discuss the interaction between them due to the relative low frequency and the limited sample size. Our findings should be validated in large population associations. Finally, in vivo and in vitro experiments are warranted to explore the potential function of the significant variants and figure out their role in lung cancer tumorigenesis. Conclusions In summary, we newly identified two NSCLC related variants on chromosome 5p15.33. Both TERT -rs33963617 and CLPTM1L -rs77518573 conferred reduced risk for NSCLC in Chinese population. Our study gives new insight into the power of low-frequency variants in explaining cancer heritability and expands our understanding about the essential role of TERT-CLPTM1L region in lung cancer development. Abbreviations GWAS, genome wide association study; NSCLC, non-small cell lung cancer; TERT, telomerase reverse transcriptase; CLPTM1L, cleft-lip and palate transmembrane protein 1-like; LD, linkage disequilibrium; HUST, Huazhong University of Science and Technology; Q-PCR, quantitative polymerase chain reaction; SNP, single nucleotide polymorphism; MAF, minor allele frequency; HWE, Hardy-Weinberg equilibrium; OR, oddsratio; CI, confidence intervals; SCC, squamous cell carcinomas. Declarations Conflicts of interest The authors declare that they have no potential conflicts of interest. Authors' Contributions Conception and design: Z. Ji, J. Li, L. Cheng Development of methodology: Z. Ji, C. Xiang, L. Cheng Acquisition of data (provided samples, acquired and managed patients, provided facilities, etc.): Z. Ji, Y. Li, X. Luo, P. Yuan, J. Long, N. Shen, Y. Shen, L. Deng, J. Li, L. Cheng Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): Z. Ji, Y. Li, J. Li, L. Cheng Writing, review, and/or revision of the manuscript: Z. Ji, J. Li, L. Cheng Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): Y. Li, C. Xiang, J. Li, L. Cheng Study supervision: J. Li, L. Cheng Funding information This work was supported by the National Natural Science Foundation of China (Grant numbers: 81572071). Acknowledgments This work was supported by the National Natural Science Foundation of China (81572071). We thank all the staffs of laboratory medicine whose contributions made this work possible. Data availability statement The data used to support the findings of this study are available from the corresponding author upon request. References Siegel RL, Miller KD, Jemal A: Cancer statistics, 2019 . CA Cancer J Clin 2019, 69 (1):7-34. 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Zhu M, Geng L, Shen W, Wang Y, Liu J, Cheng Y, Wang C, Dai J, Jin G, Hu Z et al : Exome-Wide Association Study Identifies Low-Frequency Coding Variants in 2p23.2 and 7p11.2 Associated with Survival of Non-Small Cell Lung Cancer Patients . J THORAC ONCOL 2017, 12 (4):644-656. Zhao Y, Chen G, Zhao Y, Song X, Chen H, Mao Y, Lu D: Fine-mapping of a region of chromosome 5p15.33 (TERT-CLPTM1L) suggests a novel locus in TERT and a CLPTM1L haplotype are associated with glioma susceptibility in a Chinese population . INT J CANCER 2012, 131 (7):1569-1576. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K: dbSNP: the NCBI database of genetic variation . NUCLEIC ACIDS RES 2001, 29 (1):308-311. Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Hoover J et al : ClinVar: public archive of interpretations of clinically relevant variants . NUCLEIC ACIDS RES 2016, 44 (D1):D862-D868. Martinez P, Blasco MA: Telomere-driven diseases and telomere-targeting therapies . J CELL BIOL 2017, 216 (4):875-887. Tummala H, Walne A, Collopy L, Cardoso S, de la Fuente J, Lawson S, Powell J, Cooper N, Foster A, Mohammed S et al : Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita . J CLIN INVEST 2015, 125 (5):2151-2160. Shay JW: Role of Telomeres and Telomerase in Aging and Cancer . CANCER DISCOV 2016, 6 (6):584-593. Maciejowski J, de Lange T: Telomeres in cancer: tumour suppression and genome instability . Nat Rev Mol Cell Biol 2017, 18 (3):175-186. Sauna ZE, Kimchi-Sarfaty C: Understanding the contribution of synonymous mutations to human disease . NAT REV GENET 2011, 12 (10):683-691. Brest P, Lapaquette P, Souidi M, Lebrigand K, Cesaro A, Vouret-Craviari V, Mari B, Barbry P, Mosnier JF, Hebuterne X et al : A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease . NAT GENET 2011, 43 (3):242-245. Biasoli D, Compston-Garnett L, Ricketts SL, Birand Z, Courtay-Cahen C, Fineberg E, Arendt M, Boerkamp K, Melin M, Koltookian M et al : A synonymous germline variant in a gene encoding a cell adhesion molecule is associated with cutaneous mast cell tumour development in Labrador and Golden Retrievers . PLOS GENET 2019, 15 (3):e1007967. Ni Z, Chen Q, Lai Y, Wang Z, Sun L, Luo X, Wang X: Prognostic significance of CLPTM1L expression and its effects on migration and invasion of human lung cancer cells . CANCER BIOMARK 2016, 16 (3):445-452. James MA, Vikis HG, Tate E, Rymaszewski AL, You M: CRR9/CLPTM1L regulates cell survival signaling and is required for Ras transformation and lung tumorigenesis . CANCER RES 2014, 74 (4):1116-1127. Jin T, Li B, He N, Zhang Y, Xia R, Kang L, Ding Y, Yuan D: CLPTM1L polymorphism as a protective factor for lung cancer: a case-control study in southern Chinese population . Tumour Biol 2016, 37 (8):10533-10538. Zerbino DR, Achuthan P, Akanni W, Amode MR, Barrell D, Bhai J, Billis K, Cummins C, Gall A, Giron CG et al : Ensembl 2018 . NUCLEIC ACIDS RES 2018, 46 (D1):D754-D761. Myneni AA, Chang SC, Niu R, Liu L, Ochs-Balcom HM, Li Y, Zhang C, Zhao B, Shi J, Han X et al : Genetic polymorphisms of TERT and CLPTM1L and risk of lung cancer--a case-control study in a Chinese population . LUNG CANCER 2013, 80 (2):131-137. Tables Table 1. Selected characteristics of NSCLC cases and controls in this study. Stage I Stage II Combined Samples Cases Controls P Cases Controls P Cases Controls P (n=960) (n=916) (n=1596) (n=1614) (n=2556) (n=2530) Age, Mean (SD) 58.0 (9.8) 58.6 (9.5) 0.165 54.5 (7.4) 54.8 (7.6) 0.428 55.8 (8.5) 56.2 (8.6) 0.087 Gender, N (%) 0.558 0.522 0.898 Male 666 (69.4) 624 (68.1) 1033 (64.7) 1062 (65.8) 1699 (66.5) 1686 (66.6) Female 294 (30.6) 292 (31.9) 563 (35.3) 552 (34.2) 857 (33.5) 844 (33.4) Smoking status, N (%) 0.006 3.07×10 -4 0.002 Smoking 474 (49.4) 407 (44.4) 803 (50.3) 706 (43.7) 1277 (50.0) 1113 (44.0) Non-smoking 455 (47.4) 505 (55.1) 776 (48.6) 866 (53.7) 1231 (48.1) 1371 (54.2) Unknown 31 (3.2) 4 (0.4) 17 (1.1) 42 (2.6) 48 (1.9) 46 (1.8) Pathological type, N (%) AC 583 (60.7) 1016 (63.7) 1599 (62.6) SCC 309 (32.2) 415 (26.0) 724 (28.3) Others 53 (5.5) 138 (8.6) 191 (7.5) Unknown 15 (1.6) 27 (1.7) 42 (1.6) Clinical stage, N (%) Early stage * 332 (34.6) 576 (36.1) 908 (35.5) Advanced stage † 593 (61.8) 912 (57.1) 1505 (58.9) Unknown 35 (3.6) 108 (6.8) 143 (5.6) AC, adenocarcinoma; SCC, squamous cell carcinomas * : Early stage included stage 0, I and II. † : Advanced stage included stage III and stage IV. Table 2. Association between candidate variants and lung cancer risk. Position SNP Gene Location Ref/Alt MAF OR (95% CI) * P † Cases Controls chr5:1268624 rs180675821 TERT intronic G/A 0.016 0.011 1.46 (0.82-2.61) 0.201 chr5:1279439 rs33963617 TERT synonymous G/A 0.050 0.072 0.71 (0.53-0.94) 0.018 chr5:1320880 rs74368690 CLPTM1L intronic G/A 0.011 0.015 0.77 (0.43-1.38) 0.376 chr5:1343620 rs552616298 CLPTM1L intronic A/T 0.014 0.019 0.80 (0.48-1.36) 0.417 chr5:1346773 rs77518573 CLPTM1L Upstream C/A 0.069 0.097 0.68 (0.53-0.88) 0.003 * : Adjusted for age, gender and smoking status. † : P values alculated by a dominant model in logistic regression adjusted by sex, age and smoking status. Table 3. The associations between rs33963617 and rs77518573 with NSCLC risk in Stage I, Stage II and combined samples. rs33963617 rs77518573 Genotype Cases Controls OR (95% CI) * P Genotype Cases Controls OR (95% CI) * P Stage I GG 861 785 1 CC 832 735 1 AG 91 117 0.72 (0.54-0.97) 0.030 AC 121 157 0.69 (0.53-0.89) 0.040 AA 3 7 0.44 (0.11-1.72) 0.239 AA 6 9 0.62 (0.22-1.75) 0.363 Dominant model 0.71 (0.53-0.94) 0.018 Dominant model 0.68 (0.53-0.88) 0.003 Stage II GG 1426 1311 1 CC 1293 1245 1 AG 148 223 0.59 (0.48-0.75) 6.00×10 -6 AC 285 354 0.76 (0.64-0.91) 0.003 AA 2 4 0.45 (0.08-2.45) 0.354 AA 1 5 0.18 (0.02-1.58) 0.122 Dominant model 0.59 (0.47-0.74) 4.00×10 -6 Dominant model 0.75 (0.63-0.90) 0.002 Stage I +II GG 2287 2096 1 CC 2125 1980 1 AG 239 340 0.64 (0.54-0.77) 9.12×10 -7 AC 406 511 0.74 (0.64-0.85) 4.20×10 -5 AA 5 11 0.43 (0.15-1.25) 0.122 AA 7 14 0.47 (0.19-1.16) 0.100 Dominant model 0.63 (0.53-0.76) 3.80×10 -7 Dominant model 0.73 (0.63-0.84) 2.00×10 -5 * : Adjusted for age, gender and smoking status. Table 4. Subgroup analysis about the association between the identified variants and lung cancer. Subgroups rs33963617 rs77518573 Cases † Controls † OR (95% CI) ‡ P Cases † Controls † OR (95% CI) ‡ P Smoking status NO 1131/118 1164/192 0.65 (0.51-0.83) 0.001 1055/195 1099/295 0.68 (0.56-0.83) 1.82×10 -4 YES 1113/124 959/159 0.69 (0.54-0.89) 0.005 1030/212 900/237 0.82 (0.67-1.02) 0.075 Pathological type AC 1442/144 2096/351 0.60 (0.49-0.74) 1.00×10 -6 1349/239 1980/525 0.66 (0.56-0.79) 2.00×10 -6 SCC 642/74 2096/351 0.68 (0.52-0.90) 0.007 592/127 1980/525 0.85 (0.67-1.06) 0.148 Others 168/19 2096/351 0.67 (0.41-1.09) 0.104 151/39 1980/525 0.90 (0.62-1.30) 0.568 Clinical stage * Early stage 813/84 2096/351 0.62 (0.48-0.80) 2.27×10 -4 747/157 1980/525 0.81 (0.67-0.99) 0.044 Advanced stage 1354/140 2096/351 0.62 (0.51-0.77) 8.00×10 -6 1260/233 1980/525 0.69 (0.58-0.81) 1.60×10 -5 AC, adenocarcinoma; SCC, squamous cell carcinomas * : Early stage included stage 0, I and II, and advanced stage included stage III and IV. † : Wild-type homozygote/Heterozygote and variant homozygote. ‡ : adjusted for age, gender and smoking status under dominant model. 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Technology","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Liming","middleName":"","lastName":"Cheng","suffix":""}],"badges":[],"createdAt":"2019-07-16 18:32:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.2.11710/v1","doiUrl":"https://doi.org/10.21203/rs.2.11710/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":601324,"identity":"eea4b137-a9b0-4dbf-b916-6d3367c4f2de","added_by":"auto","created_at":"2020-03-05 16:42:22","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":71817,"visible":true,"origin":"","legend":"The cumulative effect of the two NSCLC associated polymorphisms rs33963617 and rs77518573.","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2550/v1/Figure 1.jpg"},{"id":13469942,"identity":"fa10da65-5ce5-40da-ae83-829cc8ffdc97","added_by":"auto","created_at":"2021-09-16 21:03:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1175622,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2550/v1/cdcb49b4-e989-4ee2-ad73-324495fd9d99.pdf"},{"id":601325,"identity":"629370c3-a78f-43e6-ad98-e4399dd098c7","added_by":"auto","created_at":"2020-03-05 16:42:22","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":16515,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-2550/v1/Supplement Table 1.docx"}],"financialInterests":"","formattedTitle":"Identification of two novel susceptibility variants on chromosome 5p15.33 for non-small cell lung cancer in Chinese population","fulltext":[{"header":"Background","content":"\u003cp\u003eLung cancer is the most common diagnosed malignancy around the world.[1] In China, the morbidity and mortality of lung cancer ranks the first among various malignancies, with an estimated 733,300 new cases and 610,200 deaths in 2015.[2] Environmental factors such as unhealthy lifestyle, fine-particulate air pollution and occupational exposure play the primary role in causing sporadic lung cancer.[3-5] Epidemiological investigations have showed that about one fifth lung cancers were attributable to cigarette smoking.[6] However, only a small proportion of the smokers would be suffered from lung cancer during whole lifetime, suggesting that genetic background might be a noticeable reason influencing the individual susceptibility to this disease.[7]\u003c/p\u003e\n\u003cp\u003eIn recent years, genome-wide association studies (GWAS) have revealed amounts of gene loci predisposing for multiple malignancies in different populations. Chromosome 5p15.33 has been reported as a pleiotropic locus which associated with a variety of tumors such as lung cancer, glioma, breast cancer, ovarian cancer, and pancreatic cancer.[8-11] The discovery of the lung cancer susceptibility variants such as rs2736100 and rs401681 indicated this region might play an important role in lung cancer development.[12, 13] There are two plausible genes in chromosome 5p15.33, namely, the telomerase reverse transcriptase (\u003cem\u003eTERT\u003c/em\u003e) gene and the cleft and palate transmembrane1 like (\u003cem\u003eCLPTM1L\u003c/em\u003e) gene. The gene \u003cem\u003eTERT\u003c/em\u003e encodes a catalytic subunit of telomerase reverse transcriptase which participated in maintaining the stability of chromosomes and ensuring the integrity of genetic information.[14] Telomerase was usually suppressed and inactive in most of the matured somatic cells, while about 85% of tumor cells could detect telomerase activity in varying degrees, suggesting a crucial role of \u003cem\u003eTERT\u003c/em\u003e in emergence of tumors.[15, 16] \u003cem\u003eCLPTM1L\u003c/em\u003e encodes a highly conserved transmembrane protein which was implicated in cell apoptosis and over-expressed in lung cancer tissues.[17, 18] Although systematic fine-mapping has been conducted to prioritize and characterize the causal variants in this region, the underling carcinogenic mechanisms have not been fully understood until now.[19, 20]\u003c/p\u003e\n\u003cp\u003eIn our previous study, we performed a targeted sequencing based approach on \u003cem\u003eTERT-CLPTM1L\u003c/em\u003e region to identify NSCLC associated common (minor allele frequency (MAF) \u0026ge; 5.0%) variants and found that single nucleotide polymorphism (SNP) rs7726159 conferred lung cancer risk might by affecting MYC binding and inducing telomere lengthening.[21] However, evidences suggested that in addition to common variants, polymorphisms with low-frequency can also contribute to cancer susceptibility.[22, 23] To uncover the NSCLC related low frequency variants, we systematically assessed the association of low-frequency genetic variants in \u003cem\u003eTERT-CLPTM1L\u003c/em\u003e region with the risk of NSCLC in a Chinese population in this study. Candidate variants were selected by comparing the frequency of low-frequency variants in 400 NSCLC patients scanned by previous targeted sequencing with that of East Asians (EAS) from The genome Aggregation Database (gnomAD). The relationships between candidate variants and NSCLC were further estimated by conducting a two-stage case-control study with a total of 2,556 NSCLC patients and 2,530 healthy controls.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e2.1. Study subjects\u003c/p\u003e\n\n\u003cp\u003eAs mentioned before, we enrolled 400 newly diagnosed NSCLC patients for targeted sequencing and acquired the spectrum of variation on chromosome 5p15.33.[21] In this study, we recruited a total of 2,556 patients with NSCLC and 2,530 healthy controls, partly contained in our previous study, to discover and validate the population associations. Patients were enrolled continuously from the Tongji Hospital of Huazhong University of Science and Technology (HUST), Wuhan, China during Jan 2014 to Jan 2018. Primary NSCLC cases with histological or cytological confirmation were eligible, while patients with previous cancer history, metastatic NSCLC from other organs, and previous treatment with radiotherapy or chemotherapy were excluded. Healthy controls with no history of malignant tumors and major diseases were randomly selected from subjects who went to the check-up center at the same hospital during the same time as the cases recruited. All the controls were frequency matched to the cases by age and gender. Three milliliter peripheral venous blood of all participants were collected in tubes with EDTA anticoagulant and stored freezingly at -80℃. All the participants received written informed consent and interviewed face-to-face on a standard questionnaire about basic demographic characteristics. This study was approved by the Institutional Review Committee of the Tongji Hospital, Tongji Medical College, HUST. \u003c/p\u003e\n\n\u003cp\u003e1.2. Selection of the candidate SNPs\u003c/p\u003e\n\n\u003cp\u003eBased on the results of targeted sequencing in our previous research,[21] we captured a total of 1,478 variants on chromosome 5p15.33 in 400 NSCLC patients. One thousand two hundred and fifteen variants were removed according to their rare frequency (MAF＜1.0%). Among the remaining SNPs, 237 variants got through the quality control and 31 of them were defined as low-frequency variants with MAFs range from 1% to 5%. We thus downloaded the genotype frequency data of these 31 variants in 1,008 East Asians from gnomAD and compared each variant with frequency of our NSCLC patients. Significant variants in comparisons were selected as candidates.\u003c/p\u003e\n\n\u003cp\u003e1.3. DNA extraction and genotyping\u003c/p\u003e\n\n\u003cp\u003eThe RelaxGene Blood DNA system DP349-02 (TIANGEN, Beijing, China) was used to extract genomic DNA from peripheral blood. The candidate SNPs were genotyped using the TaqMan SNP genotyping analysis on the ABI ViiA\u003csup\u003eTM\u003c/sup\u003e7 Real-Time PCR System (Applied Biosystems, Foster City, CA, USA). All assays were performed on 384-well plates with mixed cases and controls. Positive and negative samples were used for quality control on each plate. Ten percent samples were randomly selected for repetition, and the coincidence rate reached 98%.\u003c/p\u003e\n\n\u003cp\u003e1.4. Statistical analyses\u003c/p\u003e\n\n\u003cp\u003eUnpaired student’s t-test was utilized to compare the distribution of continuous variable (age) between cases and controls. And Pearson’s χ-square test was used to evaluate the difference of categorical variables about demographic characteristics (gender and smoking status) as well as genotypes in two groups. Hardy-Weinberg equilibrium (HWE) was calculated for each variant by using goodness-of-fit χ-square test among controls. Unconditional multivariate logistic regression was used to evaluate the effect of candidate variants on NSCLC susceptibility in total and subgroups analysis. All statistical analyses were performed in SPSS 21.0, and two-sided \u003ci\u003eP\u003c/i\u003e value less than 0.05 was considered statistically significant.\u003c/p\u003e\n"},{"header":"Results","content":"\u003cp\u003e3.1. Characteristics of the study subjects\u003c/p\u003e\n\n\u003cp\u003eThe demographic characteristics of all subjects and the basic clinical features about the NSCLC patients are shown in Table 1. A total of 2,556 NSCLC cases and 2,530 healthy controls were included in this study. In discovery stage with 960 cases and 916 controls, 69.4% of the patients diagnosed with NSCLC were males, and in healthy controls, males occupied a percentage of 68.1%. The mean (SD) age of the case and control groups were 58.0 (9.8) years and 58.6 (9.5) years, respectively. In the replication stage, we enrolled 1,596 NSCLC cases and 1,614 healthy controls. The mean (SD) age was 54.5 (7.4) in cases and 54.8 (7.6) in controls. Males accounted for 64.7% among cases compared with 65.8% among controls. When combining the two stages, there were no significant differences in distribution of gender (66.5% males in cases, 66.6% males in controls, \u003ci\u003eP\u003c/i\u003e = 0.898) and age (55.8±8.5 years for cases, 56.2±8.6 years for controls, \u003ci\u003eP\u003c/i\u003e = 0.087) between two groups. It's worth noting that more smokers were observed in NSCLC patients than healthy controls in both the two stages (\u003ci\u003eP\u003c/i\u003e values being 0.006 for discovery stage and 3.07×10\u003csup\u003e-4 \u003c/sup\u003efor replication stage) as well as the combined samples (\u003ci\u003eP \u003c/i\u003e= 0.002). Besides, more than 60% of the tumors were confirmed as adenocarcinomas and about 30% were squamous cell carcinomas (SCC), while the remaining cancers were other non-small cell histological types. Based on the Lung Cancer TNM classification criteria (IASLC 2009), 35.5% of the total NSCLC patients were diagnosed in an early stage (0, I or II stages) and 58.9% cases were in late stage (III and IV stages).\u003c/p\u003e\n\n\u003cp\u003e1.5. Screening of the candidate variants\u003c/p\u003e\n\n\u003cp\u003eAmong the 31 low-frequency variants identified by sequencing in our NSCLC patients, seven variants were statistically significant when comparing their frequency with that of the East Asians from gnomAD (Supplementary Table 1). We therefore selected these seven SNPs as our candidate variants. However, two of the candidates which located in segmentally duplicated regions were failed in prob design, thus the remaining 5 polymorphisms were successfully genotyped and further analyzed.\u003c/p\u003e\n\n\u003cp\u003e1.6. Association between candidate SNPs and NSCLC susceptibility\u003c/p\u003e\n\n\u003cp\u003eIn the discovery stage, we assessed the associations between 5 candidate variants and NSCLC susceptibility in 960 cases and 916 controls. As shown in Table 2, two polymorphisms were significantly associated with NSCLC risk, including rs33963617 (OR = 0.71, 95%CI: 0.53-0.94, \u003ci\u003eP\u003c/i\u003e = 0.018 in dominant model) and rs77518573 (OR = 0.68, 95%CI: 0.53-0.88, \u003ci\u003eP\u003c/i\u003e = 0.003 in dominant model). No significant association was observed between the other three variants and risk of NSCLC in this population. Based on these findings, we further validated the two promising associations in a replicated case-control study with a total of 1,596 cases and 1,614 controls. As a result, the two SNPs exhibited consistent significant relationships with NSCLC, with the estimated ORs being 0.59 (95%CI: 0.47-0.74, \u003ci\u003eP\u003c/i\u003e = 4.00×10\u003csup\u003e-6\u003c/sup\u003e) for \u003ca name=\"OLE_LINK6\"\u003e\u003c/a\u003e\u003ca name=\"OLE_LINK5\"\u003ers33963617\u003c/a\u003e and 0.75 (95%CI: 0.63-0.90, \u003ci\u003eP\u003c/i\u003e = 0.002) for rs77518573 under a dominant model. The associations retained significant when combining the samples of the two stages together (Table 3). People carrying the rs33963617 AG or AA genotypes had a reduced risk for NSCLC comparing with subjects harboring the GG homozygotes (OR = 0.63, 95% CI: 0.53-0.76, \u003ci\u003eP\u003c/i\u003e = 3.80×10\u003csup\u003e-7\u003c/sup\u003e). As for rs77518573, a protective effect towards NSCLC was also observed in subjects carrying the minor allele: comparing with the wild CC genotype, the variant genotypes (AC or AA) conferred a significant decline in NSCLC risk (OR = 0.73, 95%CI: 0.630-0.84, \u003ci\u003eP \u003c/i\u003e= 2.00×10\u003csup\u003e-5\u003c/sup\u003e). However, the impact of the mutant homozygotes seemed non-significant for both two variants owing to their scarcity in population.\u003c/p\u003e\n\n\u003cp\u003eSince the two significant variants, rs33963617 and rs77518573, were adjacent with a physical distance of about 67 kb on chromosome location, we next examined whether these variants have cumulative association by counting the number of associated alleles in each subject. Individuals carrying more than one minor allele conferred significant reduced risk than those carrying no minor allele at the two variants, and there was a gradual decrease in OR with a greater number of minor alleles (Figure 1). Specifically, compared with individuals carrying no minor allele, individuals carrying one, two or more minor alleles had an adjusted OR of 0.75 (95% CI: 0.66-0.85, \u003ci\u003eP\u003c/i\u003e = 1.10×10\u003csup\u003e-5\u003c/sup\u003e) and 0.34 (95% CI: 0.23-0.49, \u003ci\u003eP\u003c/i\u003e = 1.06×10\u003csup\u003e-8\u003c/sup\u003e), respectively.\u003c/p\u003e\n\n\u003cp\u003eStratification was primarily implemented by smoking status according to the deleterious influence of smoking on lung cancer (Table 4). Among non-smokers, both the variants showed protective effects against NSCLC, with the adjusted ORs being 0.65 (95%CI: 0.51-0.83, \u003ci\u003eP\u003c/i\u003e = 0.001) for rs33963617 and 0.68 (95%CI: 0.56-0.83, \u003ci\u003eP\u003c/i\u003e = 1.82×10\u003csup\u003e-4\u003c/sup\u003e) for rs77518573. Smokers with the variant genotypes of rs33963617 exhibited significant reduced risk of NSCLC compared with smokers harboring the wild-type genotype (OR = 0.69, 95% CI: 0.54-0.89, \u003ca name=\"OLE_LINK8\"\u003e\u003c/a\u003e\u003ca name=\"OLE_LINK7\"\u003e\u003ci\u003eP\u003c/i\u003e = 0.005\u003c/a\u003e). While for rs77518573, we observed a marginal effect in smokers, with OR of 0.82 (95%CI: 0.67-1.02, \u003ci\u003eP\u003c/i\u003e = 0.075). However, no prominent interaction was found between smoking and rs77518573 (\u003ci\u003eP\u003c/i\u003e = 0.404) or rs33963617 (\u003ci\u003eP\u003c/i\u003e = 0.853). When stratified the NSCLC patients by pathological type, we found remarkable and consistent associations for rs33963617 with both adenocarcinoma (OR = 0.66, 95%CI: 0.56-0.79, \u003ci\u003eP\u003c/i\u003e = 2.00×10\u003csup\u003e-6\u003c/sup\u003e) and SCC (OR = 0.68, 95%CI: 0.52-0.90, \u003ci\u003eP\u003c/i\u003e = 0.007) (Table 4). The SNP rs77518573 was confirmed significantly associated with only adenocarcinoma (OR = 0.60, 95%CI: 0.49-0.74, \u003ci\u003eP\u003c/i\u003e = 1.00×10\u003csup\u003e-6\u003c/sup\u003e) but not SCC (OR = 0.85, 95%CI: 0.67-1.06, \u003ci\u003eP\u003c/i\u003e = 0.148). \u003c/p\u003e\n"},{"header":"Discussion","content":"\u003cp\u003eGrowing evidence showed that common variants in the \u003ci\u003eTERT-CLPTM1L\u003c/i\u003e region account for the bulk of malignancies including NSCLC, while comprehensive investigation is limited about disease-related low-frequency variants in this region. In current study, a targeted-sequencing based approach was performed to identify low frequency variants contributing to NSCLC. Genotyping in two stage case-control studies revealed that two genetic variants, rs33963617 and rs77518573 were significantly associated with NSCLC in Chinese population. Moreover, a significant cumulative effect with the risk of NSCLC reducing was illustrated as the number of variant genotypes increased.\u003c/p\u003e\n\n\u003cp\u003eDuring the past decade, GWASs have demonstrated dozens of genetic loci which predisposing to lung cancer. However, the known common variants identified by GWASs are collectively responsible for less than 30% of lung cancer heritability, indicating much of the genetic architecture to lung cancer remains unexplained.[24] Except for common variants, low frequency variants have been proposed as a portion source of heritability and therefore may be associated with the risk of complex diseases.[25, 26]Exome-wide scan and sequencing based approaches are commonly used strategies to assess the relationship of low-frequency and rare variants with cancer or other complex traits.[27, 28] To date, several low-frequency variants have been uncovered to be associated with lung cancer susceptibility and even prognosis.[29, 30] Fine-mapping based on deep sequencing of the chromosome 5p15.33 has been conducted to define the causal lung cancer susceptibility loci.[19, 20, 31] However, little attention has been drawn to the characterization of the disease associated low-frequency variants in this region. Our study provides compelling evidence that low-frequency variants within \u003ci\u003eTERT-CLPTM1L\u003c/i\u003e, a well known GWAS locus on chromosome 5p15.33, can modulate risk of NSCLC in a Chinese population. These findings support an important role of low-frequency variants in lung cancer development and shed light on their capacity in explicating the missing heritability of complex traits.\u003c/p\u003e\n\n\u003cp\u003eThe beneficial effects of rs33963617 and rs77518573 against lung cancer were confirmed for the first time in this study. SNP rs33963617 (c.2097G\u0026gt;A, p.Ala699=) is a synonymous variant located in the 5\u003csup\u003eth\u003c/sup\u003e exon of \u003ci\u003eTERT\u003c/i\u003e gene. In particular, it is a low-frequency (MAF: 4.9%) variant in our NSCLC patients while commonly (MAF: 7.4%) arised in healthy controls. According to data from dbSNP, the frequency of this variant is much higher in East Asians (8.0%) than the other ethnic populations such as Europeans (0.7%), Africans (0.2%) and Americans (0.3%).[32]Therefore, the prominent association between rs33963617 and NSCLC risk may be specific in Chinese population considering the allelic discrepancy among different populations. Although no significant association with cancer has been reported previously, we found that rs33963617 was recorded in ClinVar database and annotated in relation to an inheritable disease called dyskeratosis congenital.[33] Intriguingly, dyskeratosis congenital is referred to as a telomere biology disorder accompanied with aberrant telomerase activity and telomeric imbalance which were generally driven by mutations linked to telomere maintenance.[34, 35] Telomere dysfunction can trigger cellular senescence and constitute a driving force for tumorgenesis by inducing limitless replicative potential and causing extensive genome instability, both of which were the hallmarks of cancer.[36, 37] Without changing the amino acid sequence, synonymous variant can also mediate gene regulation via transcriptional or post-transcriptional manner.[38-40] Hence, we speculate that rs33963617 may play a part in telomere biology and thus contribute to lung cancer susceptibility. However, further \u003ci\u003ein vivo\u003c/i\u003e and \u003ci\u003ein vitro\u003c/i\u003e experiments are required to arbitrate the concrete function of this variant and elucidate the potential mechanisms in tumorigenesis. \u003c/p\u003e\n\n\u003cp\u003e\u003ci\u003eCLPTM1L\u003c/i\u003e is the other candidate gene at chromosome 5p15.33, albeit not as famous as \u003ci\u003eTERT\u003c/i\u003e. The expression of this gene has been found increased in lung adenocarcinomas compared to matched normal lung tissues.[20] Meanwhile, over-expression of \u003ci\u003eCLPTM1L \u003c/i\u003epredicted a poor survival of lung cancer patients.[41] Functional characterization established a protumorigenic role of \u003ci\u003eCLPTM1L\u003c/i\u003e for Ras-driven lung cancer due to its regulation on cell survival signaling.[42] Several SNPs in the \u003ci\u003eCLPTM1L\u003c/i\u003e gene have been reported to be associated with decreased risk of lung cancer.[43] And the risk genotype at this locus rendered a cis-regulation on \u003ci\u003eCLPTM1L\u003c/i\u003e expression, suggesting a conceivable causative role of \u003ci\u003eCLPTM1L\u003c/i\u003e in cancer development.[42] In our study, we newly identified a protective effect of non-coding variant rs77518573 against NSCLC. Notably, the frequency of rs77518573 was also disparate among different populations (9.4% in East Asians, less than 1% in Africans and Europeans and absent in Americans), insinuating a particular relationship with NSCLC in Chinese population. Since situates merely 1.6 kb upstream the transcription start site (TSS) of the \u003ci\u003eCLPTM1L\u003c/i\u003e gene, the SNP \u003ca name=\"OLE_LINK19\"\u003e\u003c/a\u003e\u003ca name=\"OLE_LINK21\"\u003e\u003c/a\u003e\u003ca name=\"OLE_LINK20\"\u003ers77518573\u003c/a\u003e is supposed to be a potential regulatory variant residing in a traditional promoter element.[44] Promoter is an essential component for transcription initiation and the assembly of RNA polymerase and associated regulators. Variants in this element thus may modulate the expression of its target gene by affecting the binding of transcriptional activators or repressors. Nevertheless, whether the SNP rs77518573 mediates a regulation to \u003ci\u003eCLPTM1L\u003c/i\u003e and the underlie mechanisms need further elaboration in future.\u003c/p\u003e\n\n\u003cp\u003eWe detected an obvious cumulative effect between the significant variants \u003ci\u003eTERT\u003c/i\u003e-rs33963617 and \u003ci\u003eCLPTM1L\u003c/i\u003e-\u003ca name=\"OLE_LINK17\"\u003e\u003c/a\u003e\u003ca name=\"OLE_LINK18\"\u003ers77518573\u003c/a\u003e. This finding highlights the importance of both the \u003ci\u003eTERT\u003c/i\u003e and \u003ci\u003eCLPTM1L\u003c/i\u003e genes in lung cancer occurrence and prompts an additive or synergetic effect for non-linkaged variants in the same locus. In subgroup analysis, we observed consistent conspicuous associations with adenocarcinoma and SCC for \u003ci\u003eTERT\u003c/i\u003e-rs33963617, while only significant relation to adenocarcinoma for \u003ci\u003eCLPTM1L\u003c/i\u003e-rs77518573. Coincidentally, a previous study investigated similar results which showing concurrent associations with different histologic types of NSCLC for a common variant in \u003ci\u003eTERT\u003c/i\u003e, whereas just significant correlation with SCC for another variant in \u003ci\u003eCLPTM1L\u003c/i\u003e.[45] More than corroborate the pathological heterogeneity of lung cancers, the disparity may also remind the distinct carcinogenic mechanisms of the two genes.\u003c/p\u003e\n\n\u003cp\u003eOur study comprehensively investigated the relationship between low-frequency variants on chr5p15.33 and NSCLC susceptibility in Chinese population. Based on two stage case-control study representing a total of more than 5,000 subjects, we identified two novel NSCLC risk associated variants. Owing to the relative high variation frequency in East Asians and divergent genetic background among different populations, the significant associations with NSCLC may be specific in Chinese population. While considering the lack of the two protective alleles in races beyond yellow, people in west countries may be confronted with an elevated hazard for NSCLC by nature comparing with the people in East Asian. However, limitations should be addressed. Firstly, we scanned potential low-frequency variants in only 400 NSCLC patients which may lead to frequency departure. In fact, the significant variants were proved to be common in healthy controls though their frequency were much lower, even rare or absent, in other ethnicities. Replication of the associations may be thus required in other ethnic populations. Second, despite the prominent cumulative effect of the two significant variants, we didn’t discuss the interaction between them due to the relative low frequency and the limited sample size. Our findings should be validated in large population associations. Finally, \u003ci\u003ein vivo\u003c/i\u003e and \u003ci\u003ein vitro\u003c/i\u003e experiments are warranted to explore the potential function of the significant variants and figure out their role in lung cancer tumorigenesis. \u003c/p\u003e\n"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, we newly identified two NSCLC related variants on chromosome 5p15.33. Both \u003ci\u003eTERT\u003c/i\u003e-rs33963617 and \u003ci\u003eCLPTM1L\u003c/i\u003e-rs77518573 conferred reduced risk for NSCLC in Chinese population. Our study gives new insight into the power of low-frequency variants in explaining cancer heritability and expands our understanding about the essential role of \u003ci\u003eTERT-CLPTM1L\u003c/i\u003e region in lung cancer development. \u003c/p\u003e\n"},{"header":"Abbreviations","content":"\u003cp\u003eGWAS, genome wide association study; NSCLC, non-small cell lung cancer; TERT, telomerase reverse transcriptase; CLPTM1L, cleft-lip and palate transmembrane protein 1-like; LD, linkage disequilibrium; HUST, Huazhong University of Science and Technology; Q-PCR, quantitative polymerase chain reaction; SNP, single nucleotide polymorphism; MAF, minor allele frequency; HWE, Hardy-Weinberg equilibrium; OR, oddsratio; CI, confidence intervals; SCC, squamous cell carcinomas.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cb\u003eConflicts of interest\u003c/b\u003e\u003c/p\u003e\n\n\u003cp\u003eThe authors declare that they have no potential conflicts of interest.\u003c/p\u003e\n\n\u003cp\u003e\u003cb\u003eAuthors' Contributions\u003c/b\u003e\u003c/p\u003e\n\n\u003cp\u003eConception and design: Z. Ji, J. Li, L. Cheng\u003c/p\u003e\n\n\u003cp\u003eDevelopment of methodology: Z. Ji, C. Xiang, L. Cheng\u003c/p\u003e\n\n\u003cp\u003eAcquisition of data (provided samples, acquired and managed patients, provided facilities, etc.): Z. Ji, Y. Li, X. Luo, P. Yuan, J. Long, N. Shen, Y. Shen, L. Deng, J. Li, L. Cheng\u003c/p\u003e\n\n\u003cp\u003eAnalysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): Z. Ji, Y. Li, J. Li, L. Cheng\u003c/p\u003e\n\n\u003cp\u003eWriting, review, and/or revision of the manuscript: Z. Ji, J. Li, L. Cheng\u003c/p\u003e\n\n\u003cp\u003eAdministrative, technical, or material support (i.e., reporting or organizing data, constructing databases): Y. Li, C. Xiang, J. Li, L. Cheng\u003c/p\u003e\n\n\u003cp\u003eStudy supervision: J. Li, L. Cheng\u003c/p\u003e\n\n\u003cp\u003e\u003cb\u003eFunding information\u003c/b\u003e\u003c/p\u003e\n\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (Grant numbers: 81572071).\u003c/p\u003e\n\n\u003cp\u003e\u003cb\u003eAcknowledgments\u003c/b\u003e\u003c/p\u003e\n\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (81572071). \u003c/p\u003e\n\n\u003cp\u003eWe thank all the staffs of laboratory medicine whose contributions made this work possible.\u003c/p\u003e\n\n\u003cp\u003e\u003cb\u003eData availability statement\u003c/b\u003e\u003c/p\u003e\n\n\u003cp\u003eThe data used to support the findings of this study are available from the corresponding author upon request.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel RL, Miller KD, Jemal A: \u003cstrong\u003eCancer statistics, 2019\u003c/strong\u003e. \u003cem\u003eCA Cancer J Clin\u003c/em\u003e 2019, \u003cstrong\u003e69\u003c/strong\u003e(1):7-34.\u003c/li\u003e\n\u003cli\u003eChen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J: \u003cstrong\u003eCancer statistics in China, 2015\u003c/strong\u003e. \u003cem\u003eCA Cancer J Clin\u003c/em\u003e 2016, \u003cstrong\u003e66\u003c/strong\u003e(2):115-132.\u003c/li\u003e\n\u003cli\u003eBiesalski HK, Bueno DMB, Chesson A, Chytil F, Grimble R, Hermus RJ, Kohrle J, Lotan R, Norpoth K, Pastorino U\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eEuropean Consensus Statement on Lung Cancer: risk factors and prevention. 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\u003cstrong\u003eEnsembl 2018\u003c/strong\u003e. \u003cem\u003eNUCLEIC ACIDS RES\u003c/em\u003e 2018, \u003cstrong\u003e46\u003c/strong\u003e(D1):D754-D761.\u003c/li\u003e\n\u003cli\u003eMyneni AA, Chang SC, Niu R, Liu L, Ochs-Balcom HM, Li Y, Zhang C, Zhao B, Shi J, Han X\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eGenetic polymorphisms of TERT and CLPTM1L and risk of lung cancer--a case-control study in a Chinese population\u003c/strong\u003e. \u003cem\u003eLUNG CANCER\u003c/em\u003e 2013, \u003cstrong\u003e80\u003c/strong\u003e(2):131-137.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eTable 1.\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"line-height: 200%;\"\u003e Selected characteristics of NSCLC cases and controls in this study.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse;\" width=\"981\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 19.5pt;\"\u003e\n\u003ctd style=\"width: 64.95pt; border: none; border-top: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 75.15pt; border: none; border-top: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"100\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 170.1pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" colspan=\"3\" width=\"227\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eStage I\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; border: none; border-top: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 205.55pt; border: none; border-top: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" colspan=\"3\" width=\"274\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eStage II\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; border: none; border-top: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 191.4pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" colspan=\"3\" width=\"255\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eCombined Samples\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 18.75pt;\"\u003e\n\u003ctd style=\"width: 64.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 75.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"100\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eCases\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eControls \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid black 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" rowspan=\"2\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003cem\u003e\u003cspan style=\"line-height: 200%; color: black;\"\u003eP \u003c/span\u003e\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003cem\u003e\u003cspan style=\"line-height: 200%; color: black;\"\u003e \u003c/span\u003e\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; border: none; border-top: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eCases\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; border: none; border-top: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eControls\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid black 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" rowspan=\"2\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003cem\u003e\u003cspan style=\"line-height: 200%; color: black;\"\u003eP \u003c/span\u003e\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003cem\u003e\u003cspan style=\"line-height: 200%; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eCases\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eControls\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" rowspan=\"2\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003cem\u003e\u003cspan style=\"line-height: 200%; color: black;\"\u003eP \u003c/span\u003e\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.5pt;\"\u003e\n\u003ctd style=\"width: 64.95pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 75.15pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"100\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e(n=960)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e(n=916)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003cem\u003e\u003cspan style=\"line-height: 200%; color: black;\"\u003e \u003c/span\u003e\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e(n=1596)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e(n=1614)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e(n=2556)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e(n=2530)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 18.75pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eAge, Mean (SD)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e58.0 (9.8)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e58.6 (9.5)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.165\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e54.5 (7.4)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e54.8 (7.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.428\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e55.8 (8.5)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e56.2 (8.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.087\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 18.75pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eGender, N (%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.558\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.522\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.898\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 18.75pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eMale\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e666 (69.4)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e624 (68.1)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e1033 (64.7)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e1062 (65.8)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e1699 (66.5)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e1686 (66.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 18.75pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eFemale\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e294 (30.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e292 (31.9)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e563 (35.3)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e552 (34.2)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e857 (33.5)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e844 (33.4)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 22.5pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eSmoking status, N (%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.006\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e3.07\u0026times;10\u003csup\u003e-4\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 22.5pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.002\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 18.75pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eSmoking\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e474 (49.4)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e407 (44.4)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e803 (50.3)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e706 (43.7)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e1277 (50.0)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e1113 (44.0)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 18.75pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eNon-smoking\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e455 (47.4)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e505 (55.1)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e776 (48.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e866 (53.7)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e1231 (48.1)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e1371 (54.2)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 18.75pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eUnknown\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e31 (3.2)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e4 (0.4)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e17 (1.1)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e42 (2.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e48 (1.9)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e46 (1.8)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 18.75pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003ePathological type, N (%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 18.75pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eAC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e583 (60.7)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e1016 (63.7)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e1599 (62.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 18.75pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eSCC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e309 (32.2)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e415 (26.0)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e724 (28.3)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 18.75pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eOthers\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e53 (5.5)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e138 (8.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e191 (7.5)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 18.75pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eUnknown\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e15 (1.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e27 (1.7)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e42 (1.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 18.75pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eClinical\u0026nbsp;stage, N (%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 18.75pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eEarly stage\u003csup\u003e*\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e332 (34.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e576 (36.1)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e908 (35.5)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 18.75pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eAdvanced\u0026nbsp;stage\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e593 (61.8)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e912 (57.1)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e1505 (58.9)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 18.75pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.5pt;\"\u003e\n\u003ctd style=\"width: 140.1pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" colspan=\"2\" width=\"187\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eUnknown\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.75pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e35 (3.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.9pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e108 (6.8)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e143 (5.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.85pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"94\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: left; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003eAC, adenocarcinoma; SCC, squamous cell carcinomas\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003csup\u003e*\u003c/sup\u003e: Early stage included stage 0, I and II.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003csup\u003e\u003cspan style=\"color: black;\"\u003e\u0026dagger;\u003c/span\u003e\u003c/sup\u003e: Advanced stage included stage III and stage IV.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003cstrong\u003e\u003cspan style=\"color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003cstrong\u003e\u003cspan style=\"color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%; color: black;\"\u003eTable 2.\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"line-height: 200%; color: black;\"\u003e Association between candidate variants and lung cancer risk.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse;\" width=\"735\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 15.75pt;\"\u003e\n\u003ctd style=\"width: 77.5pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid black 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 15.75pt;\" rowspan=\"2\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003ePosition\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 73.5pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid black 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 15.75pt;\" rowspan=\"2\" width=\"98\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eSNP\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 64.15pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid black 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 15.75pt;\" rowspan=\"2\" width=\"86\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eGene\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid black 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 15.75pt;\" rowspan=\"2\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eLocation\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: .65in; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid black 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 15.75pt;\" rowspan=\"2\" width=\"62\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eRef/Alt\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 90.95pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid black 1.0pt; 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geneva; color: black;\"\u003e0.80 (0.48-1.36)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 37.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 29.25pt;\" width=\"50\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.417\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 29.25pt;\"\u003e\n\u003ctd style=\"width: 77.5pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 29.25pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003echr5:1346773\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 73.5pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 29.25pt;\" width=\"98\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003ers77518573\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 64.15pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 29.25pt;\" width=\"86\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eCLPTM1L\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.5pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 29.25pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eUpstream\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: .65in; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 29.25pt;\" width=\"62\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eC/A\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 38.8pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 29.25pt;\" width=\"52\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.069\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 52.15pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 29.25pt;\" width=\"70\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.097\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 88.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 29.25pt;\" width=\"118\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.68 (0.53-0.88)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 37.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 29.25pt;\" width=\"50\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.003\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003csup\u003e*\u003c/sup\u003e: Adjusted for age, gender and smoking status.\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003csup\u003e\u003cspan style=\"color: black;\"\u003e\u0026dagger;\u003c/span\u003e\u003c/sup\u003e: P values alculated by a dominant model in logistic regression adjusted by sex, age and smoking status.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eTable 3.\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"line-height: 200%;\"\u003e The associations between rs33963617 and rs77518573 with NSCLC risk in Stage I, Stage II and combined samples.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse;\" width=\"1037\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 16.5pt;\"\u003e\n\u003ctd style=\"width: 62.25pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid black 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 16.5pt;\" rowspan=\"3\" width=\"83\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 354.25pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 16.5pt;\" colspan=\"5\" width=\"472\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003ers33963617\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; border: none; border-top: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.5pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 347.3pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 16.5pt;\" colspan=\"5\" width=\"463\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003ers77518573\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 15.75pt;\"\u003e\n\u003ctd style=\"width: 99.1pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 15.75pt;\" rowspan=\"2\" width=\"132\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eGenotype\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 15.75pt;\" rowspan=\"2\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eCases \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 15.75pt;\" rowspan=\"2\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eControls \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 15.75pt;\" rowspan=\"2\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eOR (95% CI)\u003csup\u003e*\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 15.75pt;\" rowspan=\"2\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003cem\u003e\u003cspan style=\"line-height: 200%; color: black;\"\u003eP\u003c/span\u003e\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 15.75pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003cem\u003e\u003cspan style=\"line-height: 200%; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 15.75pt;\" rowspan=\"2\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eGenotype\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 15.75pt;\" rowspan=\"2\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eCases \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 15.75pt;\" rowspan=\"2\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eControls \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.1pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 15.75pt;\" rowspan=\"2\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eOR (95% CI)\u003csup\u003e*\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid black 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 15.75pt;\" rowspan=\"2\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003cem\u003e\u003cspan style=\"line-height: 200%; color: black;\"\u003eP\u003c/span\u003e\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 16.5pt;\"\u003e\n\u003ctd style=\"width: 14.15pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.5pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.5pt;\"\u003e\n\u003ctd style=\"width: 62.25pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"83\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eStage I\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"132\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eGG\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e861\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e785\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eCC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e832\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e735\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.5pt;\"\u003e\n\u003ctd style=\"width: 62.25pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"83\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"132\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eAG\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e91\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e117\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.72 (0.54-0.97)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: 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style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.5pt;\"\u003e\n\u003ctd style=\"width: 62.25pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"83\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"132\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eAG\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e239\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e340\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.64 (0.54-0.77)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e9.12\u0026times;10\u003csup\u003e-7\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eAC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e406\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e511\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.74 (0.64-0.85)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e4.20\u0026times;10\u003csup\u003e-5\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.5pt;\"\u003e\n\u003ctd style=\"width: 62.25pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"83\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"132\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eAA\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e5\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e11\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.43 (0.15-1.25)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.122\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eAA\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e7\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e14\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.1pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.47 (0.19-1.16)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.100 \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.5pt;\"\u003e\n\u003ctd style=\"width: 62.25pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"83\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.1pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"132\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eDominant model\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.63 (0.53-0.76)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e3.80\u0026times;10\u003csup\u003e-7\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 14.15pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"19\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eDominant model\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"57\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.7pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"76\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.1pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"123\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.73 (0.63-0.84)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e2.00\u0026times;10\u003csup\u003e-5\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003csup\u003e*\u003c/sup\u003e: Adjusted for age, gender and smoking status.\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eTable 4.\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"line-height: 200%;\"\u003e Subgroup analysis about the association between the identified variants and lung cancer.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"margin-left: 5.4pt; border-collapse: collapse;\" width=\"948\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 19.5pt;\"\u003e\n\u003ctd style=\"width: 112.85pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid black 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" rowspan=\"2\" width=\"150\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eSubgroups\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 292.7pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" colspan=\"4\" width=\"390\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003ers33963617\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 11.8pt; border: none; border-top: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" width=\"16\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 293.75pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.5pt;\" colspan=\"4\" width=\"392\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003ers77518573\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 23.25pt;\"\u003e\n\u003ctd style=\"width: 58.9pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 23.25pt;\" width=\"79\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eCases\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 64.95pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 23.25pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eControls\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 104.9pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 23.25pt;\" width=\"140\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003eOR (95% CI)\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.95pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 23.25pt;\" width=\"85\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003cem\u003e\u003cspan style=\"line-height: 200%; color: 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black;\"\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 57.95pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.25pt;\" width=\"77\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e1260/233\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 67.95pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.25pt;\" width=\"91\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e1980/525\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 104.9pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.25pt;\" width=\"140\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e0.69 (0.58-0.81)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 62.95pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.25pt;\" width=\"84\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: verdana, geneva; color: black;\"\u003e1.60\u0026times;10\u003csup\u003e-5\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003eAC, adenocarcinoma; SCC, squamous cell carcinomas\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003csup\u003e*\u003c/sup\u003e: Early stage included stage 0, I and II, and advanced stage included stage III and IV.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003csup\u003e\u003cspan style=\"color: black;\"\u003e\u0026dagger;\u003c/span\u003e\u003c/sup\u003e: Wild-type homozygote/Heterozygote and variant homozygote.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; font-family: verdana, geneva;\"\u003e\u003csup\u003e\u003cspan style=\"color: black;\"\u003e\u0026Dagger;\u003c/span\u003e\u003c/sup\u003e: adjusted for age, gender and smoking status under dominant model.\u003c/span\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"non-small cell lung cancer, 5p15.33, low frequency, genetic variant, susceptibility","lastPublishedDoi":"10.21203/rs.2.11710/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.11710/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Abstract\nBackground：Genome-wide association studies (GWAS) have identified 5p15.33 as a susceptibility locus for lung cancer. However, for non-small cell lung cancer (NSCLC), low-frequency risk variants in this region have not been systematically identified and studied. We have screened low-frequency variants on chromosome 5p15.33 in Chinese NSCLC patients by targeted sequencing before.\nMethods：In this study, we selected candidate variants from low-frequency variants by comparing the genotype frequency of 400 NSCLC patients with 1,008 East Asians from The genome Aggregation Database (gnomAD). The associations between candidate variants and NSCLC were then discovered and replicated in two case-control sets: stage I with 960 cases and 916 controls, and stage II with 1,596 cases and 1,614 controls in total.\nResults：Among the 5 candidates, 2 polymorphisms were significantly associated with risk of NSCLC, including rs33963617 (OR = 0.63, 95% CI: 0.53-0.76, P = 3.80 × 10-7) in TERT and rs77518573 (OR = 0.73, 95% CI: 0.63-0.84, P = 2.00 × 10-5) in CLPTM1L. When stratified by histologic subtype, a significant association was only investigated in adenocarcinoma for rs77518573. We also observed an obvious cumulative effect of the two significant variants.\nConclusions: We newly identified two NSCLC related variants on chromosome 5p15.33. Both TERT-rs33963617 and CLPTM1L-rs77518573 conferred reduced risk for NSCLC in Chinese population. Our study gives new insight into the power of low-frequency variants in explaining cancer heritability and expands our understanding about the essential role of TERT-CLPTM1L region in lung cancer development.\nKeywords:\nnon-small cell lung cancer, 5p15.33, low frequency, genetic variant, susceptibility","manuscriptTitle":"Identification of two novel susceptibility variants on chromosome 5p15.33 for non-small cell lung cancer in Chinese population","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2019-07-19 03:41:19","doi":"10.21203/rs.2.11710/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"dbe358b3-4bd7-4450-acd9-fca3edb1985a","owner":[],"postedDate":"July 19th, 2019","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":17350,"name":"Cancer Biology"}],"tags":[],"updatedAt":"","versionOfRecord":[],"versionCreatedAt":"2019-07-19 03:41:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2550","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-2550","version":["v1"]},"buildId":"ApUGefWb6u5IBVtyqm6d5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}