Exploring the expression and the prognosis of mismatch repair protein and PD-L1 in colorectal cancer

Exploring the expression and the prognosis of mismatch repair protein and PD-L1 in colorectal cancer | 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 Exploring the expression and the prognosis of mismatch repair protein and PD-L1 in colorectal cancer Yaping Zhang, Lu Han, Qun Zhang, Zhihao Liu, Haiqing Niu, Li Li, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2287083/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 Background Colorectal cancer (CRC) is one of the most common malignancies of the gastrointestinal tract, it is very important to find biomarkers that can accurately predict the therapeutic efficacy to accurately grasp the development of the disease, this study aims to investigate the expression and clinical significance of mismatch repair (MMR) protein and programmed cell death 1 ligand 1 (PD-L1) in samples from surgically resected colorectal cancer (CRC) patients. Methods A total of 272 surgically resected CRC patients attending at Drum Tower Hospital of Nanjing University School of Medicine from January 2018 to May 2022 were retrospectively included in the study. Collect surgical excision samples from all patients and record in detail the general data, clinicopathological data, and imaging data of all subjects. Immunohistochemistry (IHC) and Western Blot were used to detect the expression of MSH2, MSH6, MLH1, and PMS2 proteins in the tumor tissue and normal tissue adjacent to the cancer of the resected samples, respectively. X 2 test was used to investigate the correlation between the expression of MMR protein and PD-L1 in CRC tumor tissues and the clinicopathological characteristics, then further analyzed the correlation between the deletion of four MMR proteins in CRC tumor tissues, and finally investigated the relationship between the expression of MMR protein and PD-L1 and the prognosis of CRC patients by survival curve and Log Rank test. Results 1. MMR protein expression deletion was correlated with tumor location, differentiation degree, and TNM stage ( P < 0.05); while PD-L1 expression was only correlated with TNM stage ( P < 0.05). 2. Correlation analysis of MMR protein isoform expression deletion found that PMS2 expression deletion was significantly correlated with MLH1 expression deletion, similarly, MSH2 expression deletion was significantly correlated with MSH6 expression deletion was significantly correlated with MSH6 expression deletion ( P < 0.05), in addition, PMS2 expression deletion was also correlated with PD-L1 expression ( P < 0.05). 3. The survival time was shorter in dMMR patients compared with pMMR patients. Conclusion Deletion of MMR protein expression and expression of PD-L1 are closely related to clinicopathological characteristics and prognosis of CRC patients, maybe MMR and PD-L1can be potential biomarkers. Colorectal cancer PD-L1 MMR pathological features prognosis Figures Figure 1 Figure 2 Figure 3 Introduction With the continuous progress in the level of medical care, scholars have made breakthroughs in the understanding of tumor immune response, and the application of immunotherapy and immune checkpoint inhibitors (ICPIs) has rapidly become a new direction in cancer treatment [1, 2] . Germani et al. demonstrated that the patients who are microsatellite instability-high (MSI-H) / mismatch repair deficient（dMMR ）(also known as dMMR-MSI-H CRC) in metastatic colorectal cancer (mCRC) patients are more effective with programmed cell death receptor 1 (PD-1) inhibitors [3, 4] , Similarly, several prospective clinical trials of ICPIs for chemotherapy-resistant dMMR-MSI-H CRC have demonstrated high disease control rate (DCR) and good progression-free survival (PFS). However, only about 15% of CRC patients showed MSI-H/dMMR pathology and showed differences in efficacy in single-treatment studies with PD-1 inhibitors, suggesting patient and/or intra-tumor heterogeneity (ITH) [2, 3, 5-7] . In addition, the outcomes of patients with CRC treated with adjuvant chemotherapy（ACT） is not identical. Some studies have shown that CRC with dMMR/MSI-H is better treated with chemotherapy than pMMR, but the Ribic et al. study showed that MSS (pMMR) is more likely to benefit when treated with ACT [8-11] . Therefore, it is urgent to investigate ITH and find biomarkers that can accurately predict the therapeutic efficacy to accurately grasp the development of the disease. The purpose of this paper is to summarize the pathological data and clinical data of CRC patients and analyze the interrelationship between MMR, PD-L1, clinicopathological characteristics, and therapeutic efficacy. Data And Methods 1.1 General data: A total of 272 surgically resected CRC patients attending at Drum Tower Hospital of Nanjing University School of Medicine from January 2018 to May 2022 were retrospectively included in the study, approved by the hospital ethics committee and patients gave their informed consent. 1.2 Inclusion and exclusion criteria: Inclusion criteria: (1) all patients were diagnosed with CRC and underwent colorectal cancer resection with pathological confirmation of colorectal adenocarcinoma or mucinous adenocarcinoma of the colorectum; (2) none of them had undergone radiotherapy, chemotherapy, targeted, immunotherapy or other related treatments before surgery. Exclusion criteria: (1) accompanied by a history of disease that could affect tumor progression or serious diseases of important organs; (2) incomplete clinical data. 1.3 Detection method 1.3.1 Immunohistochemistry (IHC) staining of MMR proteins (MLH1, PMS2, MSH2, and MSH6): tissue wax sections, sample preparation, sample dewaxing, antigen repair, blocking of endogenous peroxidase activity, followed by addition of primary antibody (MLH1, PMS2, MSH2, MSH6 are all from Dako, Denmark, working dilution 1:200), incubation at room temperature and addition of secondary antibody (EnVisionTM Detection Kit, Dako, Glostrup, Denmark, dilution 1:200). The sections were then subjected to DAB staining, hematoxylin negative staining, conventional dehydration and then sealed with gum. A negative control group was set up for each test with phosphate buffer and a positive control group was set up for sections of clearly positive specimens. 1.3.2 IHC staining of PD-L1: Tissue wax block dewaxing, hydration, antigen repair and blocking the activities of endogenous peroxidase. The primary antibody PD-L1 was monoclonal mouse anti-human (clone number 22C3, working solution dilution 1:500), and the rest of the procedure was performed as above, and staining was performed on Dako fully automated immunohistochemistry Link48. Negative and positive controls were set up as above for each test. 1.4 Interpretation of results: IHC-stained sections were interpreted under double-blind conditions. 1.4.1 dMMR judgment criteria: the background of the positive group in the control group was used as the internal control, and the appearance of brownish-yellow granular staining in the nuclei of tumor cells was recorded as positive, while the absence of staining in the nuclei of tumor cells was recorded as negative (see Figure 1). And the absence of expression of ≥1 of the 4 MMR proteins was judged as dMMR, and all positivity was judged as pMMR. 1.4.2 PD-L1 judgment criteria: PD-L1 staining results were determined using the combined positive score (CPS), which is the ratio of tumor cells with any intensity of membrane staining, lymphocytes/macrophages with direct cytosolic/cytoplasmic staining associated with tumor cells, and surviving tumor cells multiplied by 100. It is defined as PD-L1 positive with a CPS ≥ 10 and negative with a CPS < 10. 1.5 Patient follow-up: Patients will be followed up regularly by telephone and outpatient review from the time they are discharged from the hospital after surgery, once every 3 months within 2 years after surgery, and once every 6 months after 2 years, until June 20, 2022, with the end of follow-up or death of the patient as the observation endpoint. 1.6 Statistical methods: SPSS 22.0 statistical software was used to analyze the data. Qualitative data (%) were analyzed by X 2 test, and correlation analysis of dichotomous data was performed by column correlation χ2 test, and column correlation coefficients were calculated. Kaplan-Meier method was used to plot survival curves, and survival analysis was performed by Logrank test. P < 0.05 was considered a statistically significant difference. Results 2.1 General data: Among the 272 CRC patients, 178 were male and 94 were female; 82 patients had tumours in the left-sided colon, 149 patients had tumours in the ascending colon and 41 patients had tumours in the rectum. 217 tumors were ≤5 cm in diameter and 55 were >5 cm; 96 tumors were associated with nerve invasion and 176 were without nerve invasion; 70 tumors were associated with vascular invasion and 202 were without vascular invasion; 118 tumors were associated with lymph node metastasis and 154 tumors were not associated with lymph node metastasis. The pathological types were colorectal adenocarcinoma in 269 cases, mucinous adenocarcinoma of the colorectum in 3 cases; highly differentiated in 14 cases, moderately differentiated in 194 cases, and poorly differentiated in 64 cases. There were 126 CRC patients with TNM stage I or II and 146 CRC patients with stage III or IV; 15 CRC patients with dMMR and 257 CRC patients with pMMR; 140 patients were PD-L1 positive and 132 patients were PD-L1 negative. 2.2 Relationship between the expression of MMR and PD-L1 and clinicopathological features of mCRC primary lesions: As shown in Table 1, the expression deficiency of MMR was significantly correlated with tumor location, TNM stage, and differentiation degree ( P < 0.05). Among them, the rate of dMMR was higher in patients with left-sided colon cancer than in patients with ascending colon cancer and rectal cancer; the rate of dMMR was higher in patients with poorly differentiated than in patients with moderately differentiated and highly differentiated; and the rate of dMMR was higher in patients with stage III+IV than in patients with stage I+II. In contrast, PD-L1 positivity was only associated with TNM stage ( P < 0.05), the rate of PD-L1 positivity was higher in stage III+IV patients than in stage I+II patients. Table 1 Relationship between the expression of MMR and PD-L1 and clinicopathological features of mCRC primary lesions Pathological parameters MMR X 2 P-value PD-L1 positive X 2 P-value pMMR dMMR Age <60 94 9 3.305 0.069 53 0.037 0.847 ≥60 163 6 89 Gender Male 167 11 0.437 0.508 94 0.075 0.784 Female 90 4 48 Tumor Location left 74 8 5.568 0.048* 21 1.877 0.405 Right 145 4 83 Straight 38 3 38 Tumor diameter (cm) ≤5 206 11 0.409 0.523 29 0.008 0.931 ＞5 51 4 113 Nerve Violation None 164 12 1.626 0.202 87 1.538 0.215 There are 93 3 55 Vascular invasion None 190 12 0.273 0.601 106 0.023 0.880 There are 67 3 36 Lymph node metastasis None 143 11 1.806 0.179 84 0.779 0.348 There are 114 4 58 Type of pathology Adenocarcinoma 255 14 4.505 0.157 142 3.313 0.108 Mucinous adenocarcinoma 2 1 0 Degree of differentiation High 14 0 6.460 0.027* 36 0.554 0.780 Medium 187 7 7 Low 56 8 99 TNM Staging I+II 114 3 7.241 0.007* 74 4.005 0.045* III+IV 143 12 98 2.3 Relevance of MMR protein isoform expression deficiency： As shown in Tables 2 and 3, in colorectal cancer patients, deletion of MLH1 expression correlates with the deletion of PMS2 expression (X 2 = 188.245, P < 0.05), with column correlation coefficient C = 0.640; deletion of MSH2 expression correlates with the deletion of MSH6 expression (X 2 = 120.426, P < 0.05), with column correlation coefficient C = 0.554. Table 2 Deletion of MLH1 expression correlates with the deletion of PMS2 expression (examples) MLH1 PMS2 X 2 Value P-value - + - 7 0 + 3 262 188.245 <0.05 Total 10 262 Table 3 Deletion of MSH2 expression correlates with the deletion of MSH6 expression (examples) MSH2 MSH6 X 2 Value P-value - + - 3 2 + 1 266 120.426 <0.05 Total 4 268 2.4 Correlation of MMR protein expression with PD-L1 expression: As shown in Table 2, there were 7 cases of negative MLH1 expression, 5 cases of negative MSH2 expression, 4 cases of negative MSH6 expression, and 10 cases of negative PMS2 expression in 272 CRC patients; 142 cases of positive PD-L1 expression and 130 cases of negative PD-L1 expression in 272 CRC patients (see Figure 2). Positive PD-L1 expression was significantly correlated with the absence of PMS2 expression ( P < 0.05), that is, a higher percentage of patients with negative PMS2 expression were PD-L1 positive (Table 4). Table 4 Correlation of MMR protein expression with PD-L1 expression MMR protein PD-L1 Statistical quantities P-value - + MLH1 - 1 6 3.233 0.123 + 129 136 MSH2 - 1 4 1.577 0.373 + 129 138 MSH6 - 1 3 0.845 0.624 + 129 139 PMS2 - 1 9 5.943 0.020* + 129 133 2.5 Survival analysis: As shown in Figure 3, the follow-up period of this study was 16-42 months, with 222 progression-free and 50 progression or death cases among 272 patients. Progression-free survival (PFS) was 12.75-24 months in patients with dMMR and 18-44 months in patients with pMMR. The difference in survival curves between the two groups was statistically significant (Log rank=4.118, P =0.042). Discussion Colorectal cancer (CRC) is one of the most common malignancies of the gastrointestinal tract, with the third highest incidence rate worldwide and the second leading cause of cancer-related deaths [12, 13] . As the etiology and mechanisms of CRC have been investigated, genetic variants leading to the development of CRC have become one of important mechanisms, such as the deletion of MMR protein expression [14] . The main MMR proteins related to CRC include MLH1, MSH2, MSH6, and PMS2, which are translated from a set of mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) that correct DNA mismatch base pairs in real time and restore the "messy code" to normal nucleotide sequence [15, 16] . A retrospective study by Ye Xu's team based on 834 Chinese colorectal cancer patients showed that the proportion of dMMR was about 5.6% [17] ; the results of this study, which statistically analyzed the expression of MMR protein in cancer tissues and its correlation with clinicopathology, showed that the proportion of dMMR was about 5.5%, and the results of the study confirmed the above view. Previous studies have shown that MLH1 expression deficiency is often combined with PMS2 expression deficiency, and MSH2 expression deficiency is often combined with MSH6 expression deficiency [18-20] ; in this study, the correlation of MMR protein isoform expression deficiency was found in 7 cases of MLH1, 5 cases of MSH2, 4 cases of MSH6, and 10 cases of PMS2; 7 cases of MLH1 combined with PMS2 expression deficiency (100% of MLH1 expression deficiency) and 3 cases of MSH2 combined with MSH6 expression deficiency (100% of MSH6 expression deficiency). Similarly, MSH2 expression deficiency was significantly correlated with MSH6 expression deficiency ( P < 0.05), which confirmed the results of previous studies. The reason for this may be due to the homology of MLH1 and PMS2, which can form functionally paired dimers and cause degradation of the corresponding paired dimers when one of them is mutated, similar to MSH2 and MSH6 [21, 22] . Further analysis in this study also revealed that PMS2 expression deficiency was also associated with PD-L1 expression ( P < 0.05), and Kir et al. found that PMS2 deficiency was an independent risk factor for PD-L1 positivity by analyzing 176 resected endometrial cancer specimens [23] ， similarly, Morgan et al. found that PD-L1 was more often seen in dMMR status tumors by analyzing cervical neuroendocrine carcinomas [24] . However, studies related to the relationship between PMS2 and PD-L1 in CRC tumors are rare, and the specific mechanism of this finding in this paper still needs to be investigated at a deeper level to be discovered, but to a certain extent, it provides research ideas for subsequent researchers. In addition, several studies have shown that dMMR status occurs more often in patients with ascending colon cancer as the primary site of CRC [25] . In this study, the correlation between MMR and clinical data and pathology confirmed that patients with ascending colon cancer were more likely to show dMMR than those with left-sided colon cancer or rectum, and the difference was statistically significant ( P < 0.05); in addition to the location of the tumor primary site, dMMR was also correlated with the degree of tumor differentiation and TNM stage, and patients with moderate histopathological differentiation of the tumour, TNM stage III or IV CRC were more likely to show dMMR ( P < 0.05). CRC patients with stage III or IV TNM stage were more likely to show dMMR ( P < 0.05), and the findings previously reported by Gelsimno et al. were consistent with the present study [18, 19, 26] . Despite advances in medical care that have led to significant progress in the early detection and treatment of CRC, the prognosis for CRC patients remains poor [13, 27, 28] . Approximately 40% of patients with only localized lesions at the time of initial diagnosis develop in situ or distant recurrence after treatment; approximately 20% of patients have distant metastases at the time of initial diagnosis [28, 29] . About 20% of patients have distant metastases at the time of initial diagnosis, and their 5-year survival rate is less than 20% [30] . The 5-year survival rate is less than 20%. The standard first-line treatment for CRC is the FOLOFX or XELOX regimen based on 5-fluorouracil (5-FU) in combination with oxaliplatin (Oxa), but studies have shown that the response rate of CRC patients on FOLFOX-based chemotherapy is only 10-15%, especially for mCRC treatment is particularly poor, and 5-year survival rates remain low [26, 31-33] . In the past decade, immunotherapy has made significant breakthroughs in poorly treated solid tumors such as lung cancer and melanoma [34] . Focusing on CRC treatment, immune checkpoint therapy received regulatory approval in 2017 for the treatment of CRC with severe mutations in dMMR or MSI-H [35] . However, CRC presents as a heterogeneous and polygene-driven malignant digestive tumor due to multiple mutations in CRC oncogenes and oncogenes [36] . However, due to the presence of multiple mutations in CRC oncogenes and oncogenes, CRC manifests as a heterogeneous and multigene-driven malignant digestive tumor. PD-1 and its ligand PD-L1, a significant part of the tumor immune escape mechanism, have become a hot topic of immunotherapy research in recent years as a negative immune co-stimulatory molecule [37] . PD-L1, also known as CD274 or B7-H1, is widely expressed in antigen-presenting cells (APCs), malignant cells, non-hematopoietic cells, and non-lymphoid cells as ICPIs [38, 39] . It has been shown that when PD-L1 overexpressed by tumor cells binds to PD-1 molecules on the surface of T cells infiltrated by tumor cells, it “drives” tumor cells to evade immune surveillance and further "drives" tumor development due to immune escape [40, 41] . However, PD-L1 in CRC is not a significant factor. However, the expression of PD-L1 in CRC and its correlation with the MMR status and clinical prognosis of patients are still controversial, and Sanjun Cai's team analyzed 356 CRC cases from The Cancer Genome Atlas(TCGA) database combined with 276 Chinese CRC patients, and the results showed that the higher the expression of PD-1 and PD-L1, the better the prognosis of CRC patients [42] . However, Gao et al. found that high PD-L1 expression represented poorer overall survival (OS) and progression-free survival (PFS) by analyzing data from 240 primary liver cancer patients [43, 44] . In addition, Wang et al. found that PD-L1 expression predicted a poorer prognosis of CRC by searching 7 databases (PubMed, Cochrane Library, EMBASE, Web of Science, CBM, Wanfang, and CNKI) to screen 8823 colorectal cancer patients for analysis [45-47] . Thus, to further clarify the relationship between PD-L1 expression in CRC tumor tissues and prognosis, the author retrospectively analyzed the data of 272 Chinese CRC patients with FDA-recommended PD-L1 (clone number 22C3) antibody and interpreted the PD-L1 results by CPS score for CRC, and the results showed that PD-L1 expression was only correlated with TNM stage, and tumor tissue stage the more advanced, the more PD-L1 positive expression ( P < 0.05). However, in terms of patient survival time, the data of this study only supported the difference in OS produced by MMR status, not I, i.e., shorter survival time in dMMR patients compared with pMMR patients (P < 0.05). Since this study is a retrospective study conducted in a single center with a small sample size, there are some limitations; in addition, since this study only determined the MMR status by IHC technology, no microsatellite analysis was performed, so further studies are needed to verify the findings of this experiment, to develop more effective individualized treatment plans for mCRC and even CRC patients. The results of this study are expected to be validated in future studies to develop more effective individualized treatment plans for mCRC and CRC patients. Conclusion MMR expression and PD-L1 expression in tumour tissue of CRC correlated with pathological features and MMR expression correlated with patient prognosis, pMMR patients had a better prognosis than dMMR, which means that MMR can be used as a prognostic indicator for CRC patients. Abbreviations Abbreviations Full name in English ACT Adjuvant chemotherapy APCs Antigen-presenting cells CRC Colorectal cancer CPS Combined positive score DCR Disease control rate 5-FU 5-fluorouracil dMMR Mismatch repair deficiency ICPIs Immune checkpoint inhibitors IHC Immunohistochemistry ITH Iintra-tumor heterogeneity MMR Mismatch repair MSI-H Microsatellite instability-high OS Overall survival Oxa Oxaliplatin PD-L1 Programmed cell death 1 ligand 1 pMMR Mismatch repair proficient PD-1 Programmed cell death receptor 1 PFS Progression free survival TCGA The Cancer Genome Atlas Declarations Acknowledgements Not applicable. Authors’ contributions LH drafted the manuscript, YZ, LL, JH, XS and ZD collected the related references and participated in the discussion. QZ and XQ designed this review and revised the manuscript. All authors contributed to this manuscript. All authors read and approved the final manuscript. Funding This work was supported by the Basic Research Program of Jiangsu Province in 2021 (BK20211007), Nanjing Medical Key Science and Technology Development Project（ZKX21028）. Availability of data and materials The data supporting the conclusion of this review have been included within the article. Ethics approval and consent to participate This is not applicable for this paper. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. References KISHORE C, BHADRA P. Current advancements and future perspectives of immunotherapy in colorectal cancer research [J]. Eur J Pharmacol, 2021, 893: 173819.DOI: 10.1016/j.ejphar.2020.173819 GANESH K, STADLER Z K, CERCEK A, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential [J]. Nature reviews Gastroenterology & hepatology, 2019, 16(6): 361-75.DOI: 10.1038/s41575-019-0126-x LE D T, DURHAM J N, SMITH K N, et al. 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Int J Colorectal Dis, 2021, 36(6): 1311-9.DOI: 10.1007/s00384-021-03888-9 FU Y, LIU S, ZENG S, et al. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma [J]. J Exp Clin Cancer Res, 2019, 38(1): 396.DOI: 10.1186/s13046-019-1396-4 BENSON A B, 3RD, VENOOK A P, CEDERQUIST L, et al. Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology [J]. J Natl Compr Canc Netw, 2017, 15(3): 370-98.DOI: 10.6004/jnccn.2017.0036 DIENSTMANN R, VERMEULEN L, GUINNEY J, et al. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer [J]. Nat Rev Cancer, 2017, 17(2): 79-92.DOI: 10.1038/nrc.2016.126 JIANG X, WANG J, DENG X, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape [J]. Mol Cancer, 2019, 18(1): 10.DOI: 10.1186/s12943-018-0928-4 LECOCQ Q, KEYAERTS M, DEVOOGDT N, et al. The Next-Generation Immune Checkpoint LAG-3 and Its Therapeutic Potential in Oncology: Third Time's a Charm [J]. International journal of molecular sciences, 2020, 22(1).DOI: 10.3390/ijms22010075 GAIKWAD S, AGRAWAL M Y, KAUSHIK I, et al. Immune checkpoint proteins: Signaling mechanisms and molecular interactions in cancer immunotherapy [J]. Semin Cancer Biol, 2022, 86(Pt 3): 137-50.DOI: 10.1016/j.semcancer.2022.03.014 LIZARDO D Y, KUANG C, HAO S, et al. Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: From bench to bedside [J]. Biochim Biophys Acta Rev Cancer, 2020, 1874(2): 188447.DOI: 10.1016/j.bbcan.2020.188447 PATERSON A M, BROWN K E, KEIR M E, et al. The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo [J]. J Immunol, 2011, 187(3): 1097-105.DOI: 10.4049/jimmunol.1003496 LI Y, LIANG L, DAI W, et al. Prognostic impact of programed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor infiltrating lymphocytes in colorectal cancer [J]. Mol Cancer, 2016, 15(1): 55.DOI: 10.1186/s12943-016-0539-x GAO Q, WANG X Y, QIU S J, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma [J]. Clinical cancer research : an official journal of the American Association for Cancer Research, 2009, 15(3): 971-9.DOI: 10.1158/1078-0432.Ccr-08-1608 HU K, WANG Z M, LI J N, et al. CLEC1B Expression and PD-L1 Expression Predict Clinical Outcome in Hepatocellular Carcinoma with Tumor Hemorrhage [J]. Transl Oncol, 2018, 11(2): 552-8.DOI: 10.1016/j.tranon.2018.02.010 WANG S, YUAN B, WANG Y, et al. Clinicopathological and prognostic significance of PD-L1 expression in colorectal cancer: a meta-analysis [J]. Int J Colorectal Dis, 2021, 36(1): 117-30.DOI: 10.1007/s00384-020-03734-4 ZHAO T, LI Y, ZHANG J, et al. PD-L1 expression increased by IFN-γ via JAK2-STAT1 signaling and predicts a poor survival in colorectal cancer [J]. Oncology letters, 2020, 20(2): 1127-34.DOI: 10.3892/ol.2020.11647 TANG M, ZHENG Z, SHANG J, et al. Risk Analysis of Positive PD-L1 Expression and Clinicopathological Features and Survival Prognosis in Patients with Colorectal Cancer: Systematic Review and Meta-Analysis [J]. J Healthc Eng, 2022, 2022: 8212486.DOI: 10.1155/2022/8212486 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2287083","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":153641782,"identity":"171099a2-5cef-4bfe-9645-194a6b6e260b","order_by":0,"name":"Yaping Zhang","email":"","orcid":"","institution":"Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yaping","middleName":"","lastName":"Zhang","suffix":""},{"id":153641783,"identity":"7e195941-b53e-46f6-82f1-e1f213784099","order_by":1,"name":"Lu Han","email":"","orcid":"","institution":"Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lu","middleName":"","lastName":"Han","suffix":""},{"id":153641784,"identity":"0ee31223-d4dd-4d19-b98a-1d1af37ed15d","order_by":2,"name":"Qun Zhang","email":"","orcid":"","institution":"The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qun","middleName":"","lastName":"Zhang","suffix":""},{"id":153641785,"identity":"9fa15398-ef54-4f7f-bc13-cdd1fdbb75ca","order_by":3,"name":"Zhihao Liu","email":"","orcid":"","institution":"Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhihao","middleName":"","lastName":"Liu","suffix":""},{"id":153641786,"identity":"6642753c-6503-4312-8074-cb1a1b432553","order_by":4,"name":"Haiqing Niu","email":"","orcid":"","institution":"Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Haiqing","middleName":"","lastName":"Niu","suffix":""},{"id":153641787,"identity":"ed2f2732-29fc-45e1-aac1-410152652c5a","order_by":5,"name":"Li Li","email":"","orcid":"","institution":"The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Li","suffix":""},{"id":153641788,"identity":"708f130f-51a0-4a5e-8065-87667b709eb3","order_by":6,"name":"Jing Hu","email":"","orcid":"","institution":"The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Hu","suffix":""},{"id":153641789,"identity":"4913d94a-4175-4772-9c32-9d1f398fd9c9","order_by":7,"name":"Xiao Shi","email":"","orcid":"","institution":"The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiao","middleName":"","lastName":"Shi","suffix":""},{"id":153641790,"identity":"e35139b6-ecac-4a46-b805-876f24f4f42e","order_by":8,"name":"Zhou Ding","email":"","orcid":"","institution":"The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhou","middleName":"","lastName":"Ding","suffix":""},{"id":153641791,"identity":"6c951199-ae7a-4594-9d4b-a00b15dd3bd6","order_by":9,"name":"Xiaoping Qian","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYDACZhBhAGV8YGCDcYnUwjiDKC0o2nkgNH4tBseZHz4uKLhj13ec+dlj2x18iQ3szdskGGru4NQi2cxmbDzD4FnyzMNs5sa5Z9gSG3iOlUkwHHuGUws/M4OZNI/B4WSDw0BGbhtQi0SOmQRjw2GcWtiY2b9BtQAZliAt8m/wa+Fn5gHbYmdwGMhgBNvCg1+LZDNPMdAvhxMkD/OUSfa2sRm38aQVWyQcw63F4PzxjY8L/hy25zt/fJvEz7Zjsv3shzfe+FCDWwsIgGIzseEAmH0MEpkJeDVAtNgzQLTUEFA7CkbBKBgFIxEAANzLTIxF8v1sAAAAAElFTkSuQmCC","orcid":"","institution":"The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Xiaoping","middleName":"","lastName":"Qian","suffix":""}],"badges":[],"createdAt":"2022-11-18 07:29:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2287083/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2287083/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":29450907,"identity":"acb9091e-60e7-410c-9bd5-b5dddc40e29c","added_by":"auto","created_at":"2022-11-23 20:02:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1225822,"visible":true,"origin":"","legend":"\u003cp\u003eExpression of MSH2, MSH6, MLH1 and PMS2 proteins within CRC resection samples (IHC, ×400)\u003c/p\u003e\n\u003cp\u003eNote: A, B, C, and D show negative expression levels of MSH2, MSH6, MLH1, and PMS2, respectively.\u003c/p\u003e\n\u003cp\u003eE, F, G, and H show positive expression levels of MSH2, MSH6, MLH1, and PMS2, respectively.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-2287083/v1/18ba33d471434cbdb9df723e.png"},{"id":29451774,"identity":"efc4ad75-59b6-4c58-ba47-32e22931681f","added_by":"auto","created_at":"2022-11-23 20:10:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":282671,"visible":true,"origin":"","legend":"\u003cp\u003ePD-L1 expression within CRC resection samples (IHC, ×400)\u003c/p\u003e\n\u003cp\u003eNote: A and B show negative and positive expression of PD-L1, respectively.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-2287083/v1/ae1c43a2659125f36b1f10ab.png"},{"id":29450909,"identity":"8880bd14-b167-4cc8-b09e-8830d06f6001","added_by":"auto","created_at":"2022-11-23 20:02:27","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":34917,"visible":true,"origin":"","legend":"\u003cp\u003ePost-operative survival of CRC patients in the dMMR group compared to those in the pMMR group\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-2287083/v1/2d8dcfb20e8bec1ff2beb8f6.png"},{"id":32796569,"identity":"deaf7ef0-0363-4625-853c-4d6dac892e13","added_by":"auto","created_at":"2023-02-11 17:29:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1579792,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2287083/v1/a9b2a856-dcdb-441a-973f-604733eb0583.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Exploring the expression and the prognosis of mismatch repair protein and PD-L1 in colorectal cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eWith the continuous progress in the level of medical care, scholars have made breakthroughs in the understanding of tumor immune response, and the application of immunotherapy and immune checkpoint inhibitors (ICPIs) has rapidly become a new direction in cancer treatment\u003csup\u003e[1, 2]\u003c/sup\u003e. Germani et al. demonstrated that the patients who are microsatellite instability-high (MSI-H) / mismatch repair deficient（dMMR\u0026nbsp;）(also known as dMMR-MSI-H CRC) in metastatic colorectal cancer (mCRC) patients are more effective with programmed cell death receptor 1 (PD-1) inhibitors\u003csup\u003e[3, 4]\u003c/sup\u003e,\u0026nbsp;Similarly, several prospective clinical trials of ICPIs for chemotherapy-resistant dMMR-MSI-H CRC have demonstrated high disease control rate (DCR) and good progression-free survival (PFS). However, only about 15% of CRC patients showed MSI-H/dMMR pathology and showed differences in efficacy in single-treatment studies with PD-1 inhibitors, suggesting patient and/or intra-tumor heterogeneity (ITH)\u003csup\u003e[2, 3, 5-7]\u003c/sup\u003e . In addition, the outcomes of patients with CRC treated with adjuvant chemotherapy（ACT）\u0026nbsp;is not identical. Some studies have shown that CRC with dMMR/MSI-H is better treated with chemotherapy than pMMR, but the Ribic et al.\u0026nbsp;study showed that MSS (pMMR) is more likely to benefit when treated with ACT\u003csup\u003e[8-11]\u003c/sup\u003e. Therefore, it is urgent to investigate ITH and find biomarkers that can accurately predict the therapeutic efficacy to accurately grasp the development of the disease. The purpose of this paper is to summarize the pathological data and clinical data of CRC patients and analyze the interrelationship between MMR, PD-L1, clinicopathological characteristics, and therapeutic efficacy.\u003c/p\u003e"},{"header":"Data And Methods","content":"\u003cp\u003e1.1 General data:\u0026nbsp;A total of 272 surgically resected CRC patients attending at Drum Tower Hospital of Nanjing University School of Medicine from January 2018 to May 2022 were retrospectively included in the study,\u0026nbsp;approved by the hospital ethics committee and patients gave their informed consent.\u003c/p\u003e\n\u003cp\u003e1.2 Inclusion and exclusion criteria: Inclusion criteria: (1) all patients were diagnosed with CRC and underwent colorectal cancer resection with pathological\u0026nbsp;confirmation of colorectal\u0026nbsp;adenocarcinoma or mucinous adenocarcinoma of the colorectum; (2) none of them had undergone radiotherapy, chemotherapy, targeted, immunotherapy or other related treatments before surgery. Exclusion criteria: (1) accompanied by a history of disease that could affect tumor progression or serious diseases of important organs; (2) incomplete clinical data.\u003c/p\u003e\n\u003cp\u003e1.3 Detection method\u003c/p\u003e\n\u003cp\u003e1.3.1\u0026nbsp;Immunohistochemistry (IHC)\u0026nbsp;staining of MMR proteins (MLH1, PMS2, MSH2, and MSH6): tissue wax sections, sample preparation, sample dewaxing, antigen repair, blocking of endogenous peroxidase activity, followed by addition of primary antibody (MLH1, PMS2, MSH2, MSH6 are all from Dako, Denmark, working dilution 1:200), incubation at room temperature and addition of secondary antibody (EnVisionTM Detection Kit, Dako, Glostrup, Denmark, dilution 1:200). The sections were then subjected to DAB staining, hematoxylin negative staining, conventional dehydration and then sealed with gum. A negative control group was set up for each test with phosphate buffer and a positive control group was set up for sections of clearly positive specimens.\u003c/p\u003e\n\u003cp\u003e1.3.2 IHC staining of PD-L1: Tissue wax block dewaxing, hydration, antigen repair and blocking the activities of endogenous peroxidase. The primary antibody PD-L1 was monoclonal mouse anti-human (clone number 22C3, working solution dilution 1:500), and the rest of the procedure was performed as above, and staining was performed on Dako fully automated immunohistochemistry Link48. Negative and positive controls were set up as above for each test.\u003c/p\u003e\n\u003cp\u003e1.4 Interpretation of results: IHC-stained sections were interpreted under double-blind conditions.\u003c/p\u003e\n\u003cp\u003e1.4.1 dMMR judgment criteria: the background of the positive group in the control group was used as the internal control, and the appearance of brownish-yellow granular staining in the nuclei of tumor cells was recorded as positive, while the absence of staining in the nuclei of tumor cells was recorded as negative (see Figure 1). And the absence of expression of \u0026ge;1 of the 4 MMR proteins was judged as dMMR, and all positivity was judged as pMMR.\u003c/p\u003e\n\u003cp\u003e1.4.2 PD-L1 judgment criteria: PD-L1 staining results were determined using the combined positive score (CPS), which is the ratio of tumor cells with any intensity of membrane staining, lymphocytes/macrophages with direct cytosolic/cytoplasmic staining associated with tumor cells, and surviving tumor cells multiplied by 100. It is defined as PD-L1 positive with a CPS \u0026ge; 10 and negative with a CPS \u0026lt; 10.\u003c/p\u003e\n\u003cp\u003e1.5 Patient follow-up: Patients will be followed up regularly by telephone and outpatient review from the time they are discharged from the hospital after surgery, once every 3 months within 2 years after surgery, and once every 6 months after 2 years, until June 20, 2022, with the end of follow-up or death of the patient as the observation endpoint.\u003c/p\u003e\n\u003cp\u003e1.6 Statistical methods: SPSS 22.0 statistical software was used to analyze the data. Qualitative data (%) were analyzed by X\u003csup\u003e2\u003c/sup\u003e test, and correlation analysis of dichotomous data was performed by column correlation \u0026chi;2 test, and column correlation coefficients were calculated. Kaplan-Meier method was used to plot survival curves, and survival analysis was performed by Logrank test. \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05 was considered a statistically significant difference.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e2.1 General data:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong the 272 CRC patients, 178 were male and 94 were female; 82 patients had tumours in the left-sided colon, 149 patients had tumours in the ascending colon and 41 patients had tumours in the rectum. 217 tumors were \u0026le;5 cm in diameter and 55 were \u0026gt;5 cm; 96 tumors were associated with nerve invasion and 176 were without nerve invasion; 70 tumors were associated with vascular invasion and 202 were without vascular invasion; 118 tumors were associated with lymph node metastasis and 154 tumors were not associated with lymph node metastasis. The pathological types were\u0026nbsp;colorectal adenocarcinoma\u0026nbsp;in 269 cases,\u0026nbsp;mucinous adenocarcinoma of the colorectum\u0026nbsp;in 3 cases; highly differentiated in 14 cases, moderately differentiated in 194 cases, and\u0026nbsp;poorly differentiated\u0026nbsp;in 64 cases. There were 126 CRC patients with TNM stage I or II and 146 CRC patients with stage III or IV; 15 CRC patients with dMMR and 257 CRC patients with pMMR; 140 patients were PD-L1 positive and 132 patients were PD-L1 negative.\u003c/p\u003e\n\u003cp\u003e2.2 Relationship between the expression of MMR and PD-L1 and clinicopathological features of mCRC primary lesions: \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs shown in Table 1, the expression deficiency of MMR was significantly correlated with tumor location, TNM stage, and differentiation degree (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05). Among them, the rate of dMMR was higher in patients with\u0026nbsp;left-sided colon cancer than in patients with ascending\u0026nbsp;colon cancer and rectal cancer; the rate of dMMR was higher in patients with poorly differentiated than in patients with moderately differentiated and highly differentiated; and the rate of dMMR was higher in patients with stage III+IV than in patients with stage I+II. In contrast, PD-L1 positivity was only associated with TNM stage (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05), the rate of PD-L1 positivity was higher in stage III+IV patients than in stage I+II patients.\u003c/p\u003e\n\u003cp\u003eTable 1\u0026nbsp;Relationship between the expression of MMR and PD-L1 and clinicopathological features of mCRC primary lesions\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" width=\"17.77456647398844%\"\u003e\n \u003cp\u003ePathological\u003c/p\u003e\n \u003cp\u003eparameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" width=\"22.54335260115607%\"\u003e\n \u003cp\u003eMMR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"12.283236994219653%\"\u003e\n \u003cp\u003eX\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"10.693641618497109%\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"17.341040462427745%\"\u003e\n \u003cp\u003ePD-L1 positive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"9.393063583815028%\"\u003e\n \u003cp\u003eX\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"9.971098265895954%\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"51.92307692307692%\"\u003e\n \u003cp\u003epMMR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"48.07692307692308%\"\u003e\n \u003cp\u003edMMR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003e\u0026lt;60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e3.305\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e0.069\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e0.037\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e0.847\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003e\u0026ge;60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e167\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e0.437\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e0.508\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e0.075\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e0.784\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eTumor Location\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eleft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e5.568\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e0.048*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e1.877\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e0.405\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eStraight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eTumor diameter (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003e\u0026le;5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e206\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e0.409\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e0.523\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e0.931\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003e＞5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e113\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eNerve Violation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e164\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e1.626\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e0.202\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e1.538\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e0.215\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eThere are\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eVascular invasion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e190\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e0.273\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e0.601\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e106\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e0.880\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eThere are\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eLymph node metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e1.806\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e0.179\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e0.779\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e0.348\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eThere are\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eType of pathology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eAdenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e255\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e4.505\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e0.157\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e142\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e3.313\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e0.108\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eMucinous adenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eDegree of differentiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e6.460\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e0.027*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e0.554\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e0.780\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eMedium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e187\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eTNM Staging\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eI+II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e7.241\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e0.007*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e4.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e0.045*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"17.748917748917748%\"\u003e\n \u003cp\u003eIII+IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.688311688311689%\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.966810966810966%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.265512265512266%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.678210678210679%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.316017316017316%\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.37950937950938%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.956709956709958%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e2.3 Relevance of MMR protein isoform expression deficiency：\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs shown in Tables 2 and 3, in colorectal cancer patients, deletion of MLH1 expression correlates with the deletion of PMS2 expression (X\u003csup\u003e2\u003c/sup\u003e = 188.245, \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt;\u0026nbsp;0.05), with column correlation coefficient C = 0.640; deletion of MSH2 expression correlates with the deletion of MSH6 expression (X\u003csup\u003e2\u003c/sup\u003e = 120.426, \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05), with column correlation coefficient C = 0.554.\u003c/p\u003e\n\u003cp\u003eTable 2\u0026nbsp;Deletion of MLH1 expression correlates with the deletion of PMS2 expression\u0026nbsp;(examples)\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" width=\"25.112107623318387%\"\u003e\n \u003cp\u003eMLH1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"3.587443946188341%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" width=\"33.856502242152466%\"\u003e\n \u003cp\u003ePMS2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" width=\"20.62780269058296%\"\u003e\n \u003cp\u003eX\u003csup\u003e2\u003c/sup\u003e Value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" width=\"15.022421524663677%\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7937219730941705%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.142857142857142%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"43.42857142857143%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"42.857142857142854%\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.571428571428571%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"3.5794183445190155%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" width=\"29.75391498881432%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"15.659955257270694%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"14.988814317673379%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"22.595078299776286%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"13.422818791946309%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"3.5794183445190155%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" width=\"29.75391498881432%\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"15.659955257270694%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"14.988814317673379%\"\u003e\n \u003cp\u003e262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"22.595078299776286%\"\u003e\n \u003cp\u003e188.245\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"13.422818791946309%\"\u003e\n \u003cp\u003e\u0026lt;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"3.5794183445190155%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" width=\"29.75391498881432%\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"15.659955257270694%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"14.988814317673379%\"\u003e\n \u003cp\u003e262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"22.595078299776286%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"13.422818791946309%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eTable 3 Deletion of MSH2 expression correlates with the deletion of MSH6 expression (examples)\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" width=\"29.22374429223744%\"\u003e\n \u003cp\u003eMSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" width=\"34.47488584474886%\"\u003e\n \u003cp\u003eMSH6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"21.004566210045663%\"\u003e\n \u003cp\u003eX\u003csup\u003e2\u003c/sup\u003e Value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"15.296803652968036%\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"50.33112582781457%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"49.66887417218543%\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"29.157175398633257%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.312072892938495%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"17.312072892938495%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.956719817767652%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.261958997722095%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"29.157175398633257%\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.312072892938495%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"17.312072892938495%\"\u003e\n \u003cp\u003e266\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.956719817767652%\"\u003e\n \u003cp\u003e120.426\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.261958997722095%\"\u003e\n \u003cp\u003e\u0026lt;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"29.157175398633257%\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.312072892938495%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"17.312072892938495%\"\u003e\n \u003cp\u003e268\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.956719817767652%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.261958997722095%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e2.4 Correlation of MMR protein expression with PD-L1 expression:\u003c/p\u003e\n\u003cp\u003eAs shown in Table 2, there were 7 cases of negative MLH1 expression, 5 cases of negative MSH2 expression, 4 cases of negative MSH6 expression, and 10 cases of negative PMS2 expression in 272 CRC patients; 142 cases of positive PD-L1 expression and 130 cases of negative PD-L1 expression in 272 CRC patients (see Figure 2). Positive PD-L1 expression was significantly correlated with the absence of PMS2 expression (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05), that is, a higher percentage of patients with negative PMS2 expression were PD-L1 positive (Table 4).\u003c/p\u003e\n\u003cp\u003eTable 4 Correlation of MMR protein expression with PD-L1 expression\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" width=\"21.73076923076923%\"\u003e\n \u003cp\u003eMMR protein\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"36.34615384615385%\"\u003e\n \u003cp\u003ePD-L1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"29.03846153846154%\"\u003e\n \u003cp\u003eStatistical quantities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"12.884615384615385%\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"52.91005291005291%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"47.08994708994709%\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.73076923076923%\"\u003e\n \u003cp\u003eMLH1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.23076923076923%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.115384615384617%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.03846153846154%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.884615384615385%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.73076923076923%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.23076923076923%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.115384615384617%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.03846153846154%\"\u003e\n \u003cp\u003e3.233\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.884615384615385%\"\u003e\n \u003cp\u003e0.123\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.73076923076923%\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.23076923076923%\"\u003e\n \u003cp\u003e129\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.115384615384617%\"\u003e\n \u003cp\u003e136\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.03846153846154%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.884615384615385%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.73076923076923%\"\u003e\n \u003cp\u003eMSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.23076923076923%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.115384615384617%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.03846153846154%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.884615384615385%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.73076923076923%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.23076923076923%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.115384615384617%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.03846153846154%\"\u003e\n \u003cp\u003e1.577\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.884615384615385%\"\u003e\n \u003cp\u003e0.373\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.73076923076923%\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.23076923076923%\"\u003e\n \u003cp\u003e129\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.115384615384617%\"\u003e\n \u003cp\u003e138\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.03846153846154%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.884615384615385%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.73076923076923%\"\u003e\n \u003cp\u003eMSH6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.23076923076923%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.115384615384617%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.03846153846154%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.884615384615385%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.73076923076923%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.23076923076923%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.115384615384617%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.03846153846154%\"\u003e\n \u003cp\u003e0.845\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.884615384615385%\"\u003e\n \u003cp\u003e0.624\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.73076923076923%\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.23076923076923%\"\u003e\n \u003cp\u003e129\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.115384615384617%\"\u003e\n \u003cp\u003e139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.03846153846154%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.884615384615385%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.73076923076923%\"\u003e\n \u003cp\u003ePMS2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.23076923076923%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.115384615384617%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.03846153846154%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.884615384615385%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.73076923076923%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.23076923076923%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.115384615384617%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.03846153846154%\"\u003e\n \u003cp\u003e5.943\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.884615384615385%\"\u003e\n \u003cp\u003e0.020*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.73076923076923%\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.23076923076923%\"\u003e\n \u003cp\u003e129\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.115384615384617%\"\u003e\n \u003cp\u003e133\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.03846153846154%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.884615384615385%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e2.5 Survival analysis:\u003c/p\u003e\n\u003cp\u003eAs shown in Figure 3, the follow-up period of this study was 16-42 months, with 222 progression-free and 50 progression or death cases among 272 patients. Progression-free survival (PFS) was 12.75-24 months in patients with dMMR and 18-44 months in patients with pMMR. The difference in survival curves between the two groups was statistically significant (Log rank=4.118, \u003cem\u003eP\u003c/em\u003e=0.042).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eColorectal cancer (CRC) is one of the most common malignancies of the gastrointestinal tract, with the third highest incidence rate worldwide and the second leading cause of cancer-related deaths\u003csup\u003e[12, 13]\u003c/sup\u003e. As the etiology and mechanisms of CRC\u0026nbsp;have been investigated, genetic variants leading to the development of CRC have become one of important mechanisms, such as the deletion of MMR protein expression\u003csup\u003e[14]\u003c/sup\u003e. The main MMR proteins related to CRC include MLH1, MSH2, MSH6, and PMS2, which are translated from a set of mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) that correct DNA mismatch base pairs in real time and restore the \u0026quot;messy code\u0026quot; to normal nucleotide sequence\u003csup\u003e[15, 16]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eA retrospective study by Ye Xu\u0026apos;s team based on 834 Chinese colorectal cancer patients showed that the proportion of dMMR was about 5.6%\u003csup\u003e[17]\u003c/sup\u003e; the results of this study, which statistically analyzed the expression of MMR protein in cancer tissues and its correlation with clinicopathology, showed that the proportion of dMMR was about\u0026nbsp;5.5%, and the\u0026nbsp;results of the study confirmed the above view. Previous studies have shown that MLH1 expression deficiency is often combined with PMS2 expression deficiency, and MSH2 expression deficiency is often combined with MSH6 expression deficiency\u003csup\u003e[18-20]\u003c/sup\u003e; in this study,\u0026nbsp;the correlation of MMR protein isoform expression deficiency was found in 7 cases of MLH1, 5 cases of MSH2, 4 cases of MSH6, and 10 cases of PMS2; 7 cases of MLH1 combined with PMS2 expression deficiency (100% of MLH1 expression deficiency) and 3 cases of MSH2 combined with MSH6 expression deficiency (100% of MSH6 expression deficiency).\u0026nbsp;Similarly, MSH2 expression deficiency was significantly correlated with MSH6 expression deficiency (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05), which confirmed the results of previous studies. The reason for this may be due to the homology of MLH1 and PMS2, which can form functionally paired dimers and cause degradation of the corresponding paired dimers when one of them is mutated, similar to MSH2 and MSH6\u003csup\u003e[21, 22]\u003c/sup\u003e.\u0026nbsp;Further analysis in this study\u0026nbsp;also revealed that\u0026nbsp;PMS2 expression\u0026nbsp;deficiency was\u0026nbsp;also\u0026nbsp;associated\u0026nbsp;with\u0026nbsp;PD-L1 expression (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05), and Kir et al. found that PMS2 deficiency was an independent risk factor for PD-L1 positivity by analyzing 176 resected endometrial cancer specimens\u003csup\u003e[23]\u003c/sup\u003e，\u0026nbsp;similarly, Morgan et al. found that PD-L1 was more often seen in dMMR status tumors by analyzing cervical neuroendocrine carcinomas\u003csup\u003e[24]\u003c/sup\u003e. However, studies related to the relationship between PMS2 and PD-L1 in CRC tumors are rare, and the specific mechanism of this finding in this paper still needs to be investigated at a deeper level to be discovered, but to a certain extent, it provides research ideas for subsequent researchers.\u003c/p\u003e\n\u003cp\u003eIn addition, several studies have shown that dMMR status occurs more often in patients with\u0026nbsp;ascending\u0026nbsp;colon cancer\u0026nbsp;as the primary site of CRC\u003csup\u003e[25]\u003c/sup\u003e. In this study, the correlation between MMR and clinical data and pathology confirmed that patients with\u0026nbsp;ascending\u0026nbsp;colon cancer\u0026nbsp;were more likely to show dMMR than those with\u0026nbsp;left-sided colon cancer\u0026nbsp;or rectum, and the difference was statistically significant\u0026nbsp;(\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05); in addition to the location of the tumor primary site, dMMR was also\u0026nbsp;correlated with the\u0026nbsp;degree of tumor differentiation and TNM stage, and patients with moderate histopathological differentiation of the tumour, TNM stage III or IV CRC were more likely to show dMMR (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05). CRC patients with stage III or IV TNM stage were more likely to show dMMR (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05), and the findings previously reported by Gelsimno et al. were consistent with the present study\u003csup\u003e[18, 19, 26]\u003c/sup\u003e .\u003c/p\u003e\n\u003cp\u003eDespite advances in medical care that have led to significant progress in the early detection and treatment of CRC, the prognosis for CRC patients remains poor\u003csup\u003e[13, 27, 28]\u003c/sup\u003e.\u0026nbsp;Approximately 40% of patients with only localized lesions at the time of initial diagnosis develop in situ or distant recurrence after treatment; approximately 20% of patients have distant metastases at the time of initial diagnosis\u003csup\u003e[28, 29]\u003c/sup\u003e. About 20% of patients have distant metastases at the time of initial diagnosis, and their 5-year survival rate is less than 20%\u003csup\u003e[30]\u003c/sup\u003e. The 5-year survival rate is less than 20%. The standard first-line treatment for CRC is the FOLOFX or XELOX regimen based on 5-fluorouracil (5-FU) in combination with oxaliplatin (Oxa), but studies have shown that the response rate of CRC patients on FOLFOX-based chemotherapy is only 10-15%, especially for mCRC treatment is particularly poor, and 5-year survival rates remain low\u003csup\u003e[26, 31-33]\u003c/sup\u003e. In the\u0026nbsp;past decade, immunotherapy has made significant breakthroughs in poorly treated solid tumors such as lung cancer and melanoma\u003csup\u003e[34]\u003c/sup\u003e. Focusing on CRC treatment, immune checkpoint therapy received regulatory approval in 2017 for the\u0026nbsp;treatment of CRC with severe mutations in dMMR or MSI-H\u003csup\u003e[35]\u003c/sup\u003e. However, CRC presents as a heterogeneous and polygene-driven malignant digestive tumor due to multiple mutations in CRC oncogenes and oncogenes\u003csup\u003e[36]\u003c/sup\u003e. However, due to the presence of multiple mutations in CRC oncogenes and oncogenes, CRC manifests as a heterogeneous and multigene-driven malignant digestive tumor. PD-1 and its ligand PD-L1, a significant part of the tumor immune escape mechanism, have become a hot topic of immunotherapy research in recent years as a negative immune co-stimulatory molecule\u003csup\u003e[37]\u003c/sup\u003e.\u0026nbsp;PD-L1, also known as CD274 or B7-H1, is widely expressed in antigen-presenting cells (APCs), malignant cells, non-hematopoietic cells, and non-lymphoid cells as ICPIs\u003csup\u003e[38, 39]\u003c/sup\u003e. It has been shown that when PD-L1 overexpressed by tumor cells binds to PD-1 molecules on the surface of T cells infiltrated by tumor cells, it \u0026ldquo;drives\u0026rdquo; tumor cells to evade immune surveillance and further \u0026quot;drives\u0026quot; tumor development due to immune escape\u003csup\u003e[40, 41]\u003c/sup\u003e. However, PD-L1 in CRC is not a significant factor. However, the expression of PD-L1 in CRC and its correlation with the MMR status and clinical prognosis of patients are still controversial, and Sanjun Cai\u0026apos;s team analyzed 356 CRC cases from The Cancer Genome Atlas(TCGA) database combined with 276 Chinese CRC patients, and the results showed that the higher the expression of PD-1 and PD-L1, the better the prognosis of CRC patients\u003csup\u003e[42]\u003c/sup\u003e. However, Gao et al. found that high PD-L1 expression represented poorer overall survival (OS) and progression-free survival (PFS) by analyzing data from 240 primary liver cancer patients\u003csup\u003e[43, 44]\u003c/sup\u003e. In addition, Wang et al. found that PD-L1 expression predicted a poorer prognosis of CRC by searching 7 databases (PubMed, Cochrane Library, EMBASE, Web of Science, CBM, Wanfang, and CNKI) to screen 8823 colorectal cancer patients for analysis\u003csup\u003e[45-47]\u003c/sup\u003e. Thus, to further clarify the relationship between PD-L1 expression in CRC tumor tissues and prognosis, the\u0026nbsp;author retrospectively analyzed the data of 272 Chinese CRC patients with\u0026nbsp;FDA-recommended PD-L1 (clone number 22C3) antibody\u0026nbsp;and interpreted the PD-L1 results by CPS score for CRC, and the\u0026nbsp;results showed that\u0026nbsp;PD-L1 expression was only correlated with TNM stage, and tumor tissue stage the more advanced, the more PD-L1 positive expression (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05). However, in terms of patient survival time, the data of this study only supported\u0026nbsp;the difference in OS produced by\u0026nbsp;MMR status, not I,\u0026nbsp;i.e., shorter survival time in dMMR patients compared with pMMR patients (P \u0026lt; 0.05).\u003c/p\u003e\n\u003cp\u003eSince this study is a retrospective study conducted in a single center with a small sample size, there are some limitations; in addition, since this study only determined the MMR status by IHC technology, no microsatellite analysis was performed, so further studies are needed to verify the findings of this experiment, to develop more effective individualized treatment plans for mCRC and even CRC patients. The results of this study are expected to be validated in future studies to develop more effective individualized treatment plans for mCRC and CRC patients.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eMMR expression and PD-L1 expression in tumour tissue of CRC correlated with pathological features and MMR expression correlated with patient prognosis, pMMR patients had a better prognosis than dMMR, which means that MMR can be used as a prognostic indicator for CRC patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eAbbreviations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eFull name in English\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eACT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eAdjuvant chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eAPCs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eAntigen-presenting cells\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eCRC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eColorectal cancer\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eCPS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eCombined positive score\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eDCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eDisease control rate\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e5-FU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e5-fluorouracil\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003edMMR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eMismatch repair deficiency\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eICPIs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eImmune checkpoint inhibitors\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eIHC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eImmunohistochemistry\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eITH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eIintra-tumor heterogeneity\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eMMR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eMismatch repair\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eMSI-H\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eMicrosatellite instability-high\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eOverall survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eOxa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eOxaliplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003ePD-L1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eProgrammed cell death 1 ligand 1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003epMMR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eMismatch repair proficient\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003ePD-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eProgrammed cell death receptor 1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003ePFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eProgression free survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eTCGA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eThe Cancer Genome Atlas\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLH drafted the manuscript, YZ, LL, JH, XS and ZD collected the related references and participated in the discussion. QZ and XQ designed this review and revised the manuscript. All authors contributed to this manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Basic Research Program of Jiangsu Province in 2021 (BK20211007),\u0026nbsp;Nanjing Medical Key Science and Technology Development Project（ZKX21028）.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting the conclusion of this review have been included within the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is not applicable for this paper.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKISHORE C, BHADRA P. 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The Next-Generation Immune Checkpoint LAG-3 and Its Therapeutic Potential in Oncology: Third Time\u0026apos;s a Charm [J]. International journal of molecular sciences, 2020, 22(1).DOI: 10.3390/ijms22010075\u003c/li\u003e\n\u003cli\u003eGAIKWAD S, AGRAWAL M Y, KAUSHIK I, et al. Immune checkpoint proteins: Signaling mechanisms and molecular interactions in cancer immunotherapy [J]. Semin Cancer Biol, 2022, 86(Pt 3): 137-50.DOI: 10.1016/j.semcancer.2022.03.014\u003c/li\u003e\n\u003cli\u003eLIZARDO D Y, KUANG C, HAO S, et al. Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: From bench to bedside [J]. Biochim Biophys Acta Rev Cancer, 2020, 1874(2): 188447.DOI: 10.1016/j.bbcan.2020.188447\u003c/li\u003e\n\u003cli\u003ePATERSON A M, BROWN K E, KEIR M E, et al. The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo [J]. J Immunol, 2011, 187(3): 1097-105.DOI: 10.4049/jimmunol.1003496\u003c/li\u003e\n\u003cli\u003eLI Y, LIANG L, DAI W, et al. Prognostic impact of programed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor infiltrating lymphocytes in colorectal cancer [J]. Mol Cancer, 2016, 15(1): 55.DOI: 10.1186/s12943-016-0539-x\u003c/li\u003e\n\u003cli\u003eGAO Q, WANG X Y, QIU S J, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma [J]. Clinical cancer research : an official journal of the American Association for Cancer Research, 2009, 15(3): 971-9.DOI: 10.1158/1078-0432.Ccr-08-1608\u003c/li\u003e\n\u003cli\u003eHU K, WANG Z M, LI J N, et al. CLEC1B Expression and PD-L1 Expression Predict Clinical Outcome in Hepatocellular Carcinoma with Tumor Hemorrhage [J]. Transl Oncol, 2018, 11(2): 552-8.DOI: 10.1016/j.tranon.2018.02.010\u003c/li\u003e\n\u003cli\u003eWANG S, YUAN B, WANG Y, et al. Clinicopathological and prognostic significance of PD-L1 expression in colorectal cancer: a meta-analysis [J]. Int J Colorectal Dis, 2021, 36(1): 117-30.DOI: 10.1007/s00384-020-03734-4\u003c/li\u003e\n\u003cli\u003eZHAO T, LI Y, ZHANG J, et al. PD-L1 expression increased by IFN-\u0026gamma; via JAK2-STAT1 signaling and predicts a poor survival in colorectal cancer [J]. Oncology letters, 2020, 20(2): 1127-34.DOI: 10.3892/ol.2020.11647\u003c/li\u003e\n\u003cli\u003eTANG M, ZHENG Z, SHANG J, et al. Risk Analysis of Positive PD-L1 Expression and Clinicopathological Features and Survival Prognosis in Patients with Colorectal Cancer: Systematic Review and Meta-Analysis [J]. J Healthc Eng, 2022, 2022: 8212486.DOI: 10.1155/2022/8212486\u003c/li\u003e\n\u003c/ol\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":"Colorectal cancer, PD-L1, MMR, pathological features, prognosis","lastPublishedDoi":"10.21203/rs.3.rs-2287083/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2287083/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e \u003cb\u003eBackground\u003c/b\u003e Colorectal cancer (CRC) is one of the most common malignancies of the gastrointestinal tract, it is very important to find biomarkers that can accurately predict the therapeutic efficacy to accurately grasp the development of the disease, this study aims to investigate the expression and clinical significance of mismatch repair (MMR) protein and programmed cell death 1 ligand 1 (PD-L1) in samples from surgically resected colorectal cancer (CRC) patients.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMethods\u003c/b\u003e A total of 272 surgically resected CRC patients attending at Drum Tower Hospital of Nanjing University School of Medicine from January 2018 to May 2022 were retrospectively included in the study. Collect surgical excision samples from all patients and record in detail the general data, clinicopathological data, and imaging data of all subjects. Immunohistochemistry (IHC) and Western Blot were used to detect the expression of MSH2, MSH6, MLH1, and PMS2 proteins in the tumor tissue and normal tissue adjacent to the cancer of the resected samples, respectively. X\u003csup\u003e2\u003c/sup\u003e test was used to investigate the correlation between the expression of MMR protein and PD-L1 in CRC tumor tissues and the clinicopathological characteristics, then further analyzed the correlation between the deletion of four MMR proteins in CRC tumor tissues, and finally investigated the relationship between the expression of MMR protein and PD-L1 and the prognosis of CRC patients by survival curve and Log Rank test.\u003c/p\u003e \u003cp\u003e \u003cb\u003eResults\u003c/b\u003e 1. MMR protein expression deletion was correlated with tumor location, differentiation degree, and TNM stage (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05); while PD-L1 expression was only correlated with TNM stage (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). 2. Correlation analysis of MMR protein isoform expression deletion found that PMS2 expression deletion was significantly correlated with MLH1 expression deletion, similarly, MSH2 expression deletion was significantly correlated with MSH6 expression deletion was significantly correlated with MSH6 expression deletion (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), in addition, PMS2 expression deletion was also correlated with PD-L1 expression (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). 3. The survival time was shorter in dMMR patients compared with pMMR patients.\u003c/p\u003e \u003cp\u003e \u003cb\u003eConclusion\u003c/b\u003e Deletion of MMR protein expression and expression of PD-L1 are closely related to clinicopathological characteristics and prognosis of CRC patients, maybe MMR and PD-L1can be potential biomarkers.\u003c/p\u003e","manuscriptTitle":"Exploring the expression and the prognosis of mismatch repair protein and PD-L1 in colorectal cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-11-23 20:02:22","doi":"10.21203/rs.3.rs-2287083/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":"37a6d772-7b7d-46db-8729-c63fe3bbd3da","owner":[],"postedDate":"November 23rd, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-02-11T17:29:22+00:00","versionOfRecord":[],"versionCreatedAt":"2022-11-23 20:02:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2287083","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2287083","identity":"rs-2287083","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}