Germline Variants in DNA Repair Genes and Susceptibility to Pediatric Peripheral Neuroblastic Tumors: A Case-Controle Study

Germline Variants in DNA Repair Genes and Susceptibility to Pediatric Peripheral Neuroblastic Tumors: A Case-Controle Study | 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 Germline Variants in DNA Repair Genes and Susceptibility to Pediatric Peripheral Neuroblastic Tumors: A Case-Controle Study Beatriz Mancini Oliveira, Nathália Ondei Valle, Carlos Eduardo Coral Oliveira, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9419277/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background: Peripheral neuroblastic tumors (PNTs) are embryonal pediatric neoplasms characterized by marked clinical heterogeneity. Germline variation in DNA repair genes may influence genomic stability and modulate tumor susceptibility and disease phenotype. We evaluated the association of single nucleotide variants (SNVs) in PARP1 (rs1136410), XPC (rs2228000), and XPA (rs1800975) with PNT risk and clinicopathological characteristics in a pediatric population from Southern Brazil. Methods and Results: A case-control study was conducted including 70 cases diagnosed with neuroblastoma (NB), ganglioneuroblastoma (GNB), or ganglioneuroma (GN) at two oncology referral centers in Paraná, Brazil, and 96 controls. Genotyping was performed using validated TaqMan allelic discrimination assays, with sample sizes varying per gene due to DNA integrity constraints. Associations with disease susceptibility and clinicopathological variables were assessed using logistic regression adjusted for age and sex. No significant associations were observed for PARP1 rs1136410 or XPC rs2228000 under any genetic model evaluated. The XPA rs1800975 C allele was associated with reduced PNT susceptibility under codominant (OR=0.213; 95%CI 0.047–0.965; p=0.045) and dominant models (OR=0.228; 95%CI 0.055–0.936; p=0.040). No statistically significant associations were retained for any SNV in stratified analyses of clinicopathological variables after adjustment. Conclusions: These findings suggest that XPA rs1800975 may act as a modest modifier of PNT susceptibility in a Southern Brazilian pediatric population, while PARP1 rs1136410 and XPC rs2228000 were not associated with disease risk. Replication in larger, population-stratified cohorts is warranted to clarify the role of DNA repair gene variants in pediatric neuroblastic tumor biology. peripheral neuroblastic tumors neuroblastoma DNA repair XPA PARP1 XPC genetic susceptibility biomarkers Introduction Peripheral Neuroblastic Tumors (PNTs) are a group of embryonic neoplasms that originate from the neural crest and exhibit a broad clinical spectrum, ranging from spontaneous regression to aggressive, distant metastases. The malignant type, especially Neuroblastoma (NB), accounts for the majority of PNT cases [1].This group of tumors is characterized by marked heterogeneity, including differences in location, histopathology as classified by the Shimada System[2], biological characteristics, and prognosis[3, 4]. A major clinical challenge lies in is the high aggressiveness of specific subtypes, as approximately 50% of NB patients present with a high-risk phenotype characterized by disseminated disease and significantly low long-term survival [1, 5, 6]. Despite intensive multidisciplinary treatment, including surgery, radiotherapy, chemotherapy, and autologous hematopoietic stem cell transplantation (AHSCT), cure rates for high-risk NB patients remain below 40%[7]. Additionally, NB is responsible for about 12% of cancer-related deaths in children under 15[1]. Although much is known about acquired genomic alterations that correlate with tumor phenotype (e.g., MYCN amplification), there is a need to identify additional molecular markers that can predict disease behavior and improve treatment stratification [8]. In this context, the role of germline variants in DNA repair genes in pediatric cancers such as NB remains poorly understood. Maintenance of genomic stability is particularly critical in this setting, as PNTs arise, from neural precursors, a cell population especially vulnerable to DNA damage. DNA repair mechanisms, particularly Base Excision Repair (BER) and Nucleotide Excision Repair (NER), are essential for maintaining genomic integrity [9, 10]. Defects in these pathways can lead to accumulation of DNA damage, promoting carcinogenesis[10]. Single nucleotides variants (SNVs) in genes encoding key DNA repair proteins may alter repair efficiency and influence, cancer development and progression [11]. The PARP1 gene encodes poly (ADP-ribose) polymerase 1 (PARP1), a key member of the PARP superfamily [9]. PARP-1 acts as an immediate sensor of DNA strand breaks [12] and plays a vital role in the BER and Single Strand Break Repair (SSBR) pathways [13–15]. The protein binds to DNA breaks and immediately synthesizes poly (ADP-ribose) polymers, helping repair by recruiting essential factors, such as XRCC1, to the damage site [9]. The rs1136410 variant, located in the three prime unstranslated region (3’UTR) of the gene, has been associated with câncer susceptibility in previous studies, including to glioma, supporting further investigation of its role in PNTs [16–18] . Additionally, the XPC gene is a crucial component of the NER pathway [19]. The xeroderma pigmentosum complementation group C (XPC) protein is essential for the early damage recognition and initiation of global genome repair NER (GG-NER) [8]. Its defects are associated with an increased risk of cancer [20, 21]. The rs2228000 SNV is located in the five prime unstranslated region (5’UTR) of the gene and has been widely studied in adult cancers, such as bladder cancer [21], but its role in NB remais unclear and warrants investigation in pediatric populations. The XPA gene is another essential component of the NER pathway, necessary for GG-NER and transcription-coupled repair (TC-NER) [12, 22]. Xeroderma pigmentosum complementation group A (XPA) functions as a DNA damage recognition protein [23, 24]binding specifically to DNA lesions, likely through detection of DNA helix bending and unwinding[21]. XPA protein exists functionally as a homodimer (XPA2) and forms a complex with replication protein A (RPA) (XPA2-RPA), which increases its affinity for damaged DNA [22]. The SNV rs1800975 is located in the 5’UTR region of XPA and has been linked to cancer risk in adults, such as lung, colorectal and skin cancer[25–27] Furthermore, most existing research has concentrated on populations outside South America. Investigating these variants in a Brazilian population may provide insights into population-specific genetic contributions to disease susceptibility. This study aimed to determine whether these variants are associated with PNT susceptibility and clinical presentation and disease progression PNT susceptibility and whether they influence the clinical diversity and disease progression. Subjects and Methods Study Design and Ethical Aspects The study was approved by the Ethics Committees of the State University of Londrina (CAAE 59515722.70000.5231) and Pontifical Catholic University of Paraná (CAAE 80073124.9.0000.0020). Written informed consent was obtained from parents/guardians, and assent was provided by children aged 5 years or older. All participants were assigned anonymized codes to protect confidentiality. Participants This case-control study enrolled 96 cancer-free children recruited from routine pediatric visits at the University Hospital of the State University of Londrina (HU-UEL), Londrina, PR, Brazil (control group) and 70 pediatric patients diagnosed with neuroblastoma (NB), ganglioneuroblastoma (GNB), or ganglioneuroma (GN) recruited from the Pediatric Oncology Services at Hospital do Câncer de Londrina (HCL), Londrina, PR, Brazil and Hospital Pequeno Príncipe (HPP), Curitiba, PR, Brazil, between August 2023 and January 2025. The HCL serves as the reference oncology center for the 17th Regional Health Division of the State of Paraná, southern Brazil, providing high-complexity oncological care to patients from multiple municipalities within this region [28] . The HPP is recognized as the largest and most comprehensive pediatric hospital in Brazil [29] and has been acknowledged as one of the best pediatric hospitals in the world [30], serving patients referred from all Brazilian states. Given the rarity of PNTs, all consecutive eligible cases diagnosed during the study period were invited to participate. Tumor diagnosis was established by the attending pathologist at each participating institution. Histological classification was based on morphological criteria in accordance with the WHO Classification of Tumours [31] and the International Neuroblastoma Pathology Classification (INPC) [2], and, when available, complemented by immunohistochemical analysis [32]. Controls were selected from the same geographic region and were comparable in sex distribution. None had a prior history of cancer or other malignancy at the time of blood collection. Age and sex were included as covariates in multivariable regression models to account for potential confounding. Inclusion criteria comprised: (a) histopathological confirmation of TNPs by the attending pathologist; (b) provision of written informed consent and/or assent; and (c) availability of a peripheral blood sample or formalin-fixed paraffin-embedded (FFPE) tissue blocks. Exclusion criteria included: (a) diagnosis of other malignancies. No patients were excluded based on these criteria. Clinical, epidemiological, and pathological data were extracted from hospital records (electronic and paper-based) and are summarized in Table 2. Genomic DNA extraction For this purpose, four ML peripheral blood in tubes with ethylenediaminetetraacetic acid (EDTA) was collected from 13 patients at HCL. FFPE tissue blocks were obtained from 20 patients at HCL and 37 patients at HPP. Control samples consisted of peripheral blood from 96 children at HU-UEL. Blood samples were centrifuged at 3,500 rpm for 15 minutes, and buffy coat fractions were aliquoted and stored at −20°C for subsequent laboratory analysis. For transportation from Curitiba (HPP) to Londrina (UEL), samples were stored in a styrofoam container with dry ice to maintain temperatures below -80°C, ensuring DNA integrity. Genomic DNA was extracted using the BIOPUR MINI SPIN PLUS extraction kit (Biometrix Diagnóstica Ltda, Curitiba, Paraná, Brazil), which employs a column-based separation method, following the manufacturer's instructions with some modifications. For paraffin-embedded tissue samples, genomic DNA was extracted using the innuPREP DNA Mini kit (Analytik Jena, Jen, Germany), according to the manufacturer’s specifications. The extracted material was stored at -80°C until further use. The quantification of extracted genomic DNA was performed using a NanoDrop 2000c™ spectrophotometer (ThermoScientific, Waltman, MA, USA) at 260 nm, and the 260/280 nm ratio assessed purity. The DNA concentration was standardized to 5 ng/µL in a final volume of 100 µL for genotyping analyses. Analysis of Single Nucleotide Variants in the PARP1 , XPC and XPA Genes Variants in the PARP1 A>G (rs1136410), XPA T>C (rs1800975), and XPC G>A (rs2228000) genes were genotyped using quantitative polymerase chain reaction (qPCR) with TaqMan® probes. Validated assays were used for genotype determination (c_1515368_1_; c_482935_1_; c_16018061_10, respectively). Complete information on the variants studied is presented in Table 1. Genotyping reactions involved a final volume of 10 µL, containing 0.20 µL of allele-specific TaqMan® SNP 40× probe ( Applied Biosystems, Foster City, CA, USA ), labeled with fluorophores (VIC® and FAM®); 4.5 µL of TaqPath ProAmp Master Mix reagent ( Applied Biosystems, Foster City, CA, USA ); 0.8 µL of Buffer (Tris-EDTA); and 4.5 µL of genomic DNA at 5 ng/µL. Thermal cycling conditions included an initial denaturation at 95 °C for 10 min, followed by 50 cycles of 95 °C for 15 s and 60 °C for 1 min. Amplification and allelic discrimination were conducted using the StepOnePlus™ Real-Time PCR System ( Applied Biosystems ). Genotype calling was performed automatically and confirmed by manual inspection of allelic discrimination plots. A random subset of samples was re-genotyped for quality control, yielding 100% concordance. Table 1 - Genes, reference identification of single nucleotide variants (SNVs), chromosomal location, allelic exchange (region), and minor allele frequency (MAF) in Latin American 2 (LA2), global population (Global), and in our study. Gene and alleles Gene name SNV ID Chr. Bp/ Region MAF Pathway Global LA2 Study population PARP1 A>G poly(ADP-ribose) polymerase 1 rs1136410 chr1:226367601/ 3’UTR a A=0.8349 a G=0.1650 A=0.6252 G=0.3748 A=0.8406 G=0.1593 BER XPC G>A XPC complex subunit, DNA damage recognition and repair factor rs2228000 chr3:14158387/ 5’UTR b G=0.7580 b A=0.2419 G=0.7697 A=0.2685 G=0.7896 A=0.2103 NER XPA T>C XPA, DNA damage recognition and repair factor rs1800975 chr9:97697296/ 5’UTR c T=0.3285 c C=0.6714 T=0.3506 C=0.6494 T=0.3272 C=0.6728 NER BER: Base excision repair; LA2: Latin American individuals with predominantly European and Native American ancestry; NER: Nucleotide excision repair; UTR: untranslated region. Reference: a ALFA Project (https://www.ncbi.nlm.nih.gov/snp/rs1136410); b Reference - ALFA Project (https://www.ncbi.nlm.nih.gov/snp/rs2228000; c Reference - ALFA Project (https://www.ncbi.nlm.nih.gov/snp/rs1800975). Statistical analysis Categorical variables were compared between groups using the chi-square (χ²) test or Fisher’s exact test and are presented as absolute frequencies (n) and percentages (%). Continuous variables, such as age, were analyzed using the Mann–Whitney U test and are reported as median and interquartile range (IQR). Genotype distributions in the control group were tested for Hardy–Weinberg equilibrium (HWE) using the χ² test. The association between SNVs and PNT susceptibility was estimated using logistic regression to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) under codominant, dominant, recessive, and overdominant inheritance models. All regression analyses were adjusted for age and sex to account for potential confounding effects. Subgroup analyses were also performed according to clinicopathological characteristics. Statistical analyses were conducted using SPSS Statistics software, version 20.0 (IBM Corp., Chicago, IL, USA). A two-tailed p-value < 0.05 was considered statistically significant. Given the number of comparisons performed, no formal adjustment for multiple testing was applied, and the results should be interpreted as exploratory. Results Cohort characterization A total of 70 patients with PNTs were included, comprising 52 NB (74.3%), 9 GNB (12.9%), and 9 GN (12.9%) cases. The cohort was predominantly male (37/70, 57.8%), and the majority of NB patients presented with advanced-stage disease (III+IV, 78.4%). At last follow-up, 21 patients (30.0%) had achieved complete remission, 20 (28.6%) had died during the treatment period, and 7 (10.0%) remained under active follow-up. Missing data across clinicopathological variables primarily reflect the high rate of loss to follow-up observed in this cohort (n=22, 31.4%), as well as restricted access to paper-based or non-digitalized medical records. Detailed clinicopathological characteristics are summarized in Table 2. Table 2 - Clinicopathological characteristics of patients with Neuroblastoma (NB), Ganglioneuroblastoma (GNB), and Ganglioneuroma (GN). Parameters PNTs n=70(%) Diagnosis NB n=52(%) GNB n=9(%) GN n=9(%) Sex Male | Female 37(57.8) | 33(47.2) 27(51.9) | 25(48.1) 6(66.6) | 3(33.4) 4 (44.5) | 5 (55.5) Age at diagnosis, month ≤18months | >18months 25(35.7) | 45(64.3) 25(48.1) | 27(51.9) 0(0.0) | 9(100.0) 0(0.0) | 9(100.0) Staging I+II+IVS III+IV Unknown 19(27.1) 45(64.3) 6(8.6) 11(21.6) 41(78.4) 0(0.0) 5(55.5) 4(44.5) 0 (0.0) 3 (33.4) 0 (0.0) 6 (66.6) Death No | Yes Unknown 32(45.7) | 22(31.4) 16(22.9) 23(44.2) | 19(36.5) 9(19.3) 5(55.6) | 2(22.2) 2 (22.2) 4(44.4) | 0(100.0) 5 (55.6) Shimada classification Favorable Unfavorable Unknown 16(22.8) 11(15.8) 43(61.4) 9 (17.3) 9 (17.3) 34 (65.4) 0(0.0) 2(22.3) 7(77.7) 7(77.7) 0(0.0) 2(22.3) Histology a Undifferentiated Poorly differentiated Diferentiated Unknown 16(22.8) 16(22.8) 11(15.8) 27(38.6) 15(28.8) 14(26.9) 8(15.5) 15(28.8) 1(11.1) 2(22.2) 1(11.1) 5(55.6) 2(22.2) 0(0.0) 0(0.0) 7(77.8) CN MYCN b Median (IQR25-75) Unknown 1.510 (0.820-2.450) 44 1.850(0.820-2.900) 33 1.610(1.610-1.610) 8 1.145(0.730-1.410) 3 Metastasis at diagnosis No | Yes Unknown 41(58.6) | 27(38.6) 2(2.8) 26(50.0) | 25(48.1) 1(1.9) 8(88.9) | 1(11.1) 0(0.0) 7(77.8) | 1(11.1) 1 (11.1) Late metastasis No |Yes Unknown 45(64.3) | 24(34.3) 1(1.4) 30(57.7) | 21(40.4) 1(1.9) 6(66.7) | 3(33.3) 0(0.0) 9(100.0) | 0(0.0) 0(0.0) BM infiltration at diagnosis No | Yes Unknown 55(78.6) | 13(18.6) 2(2.8) 37(71.1) | 13(25.0) 2(3.9) 9(100.0) | 0 (0.0) 0(0.0) 9(100.0) | 0(0.0) 0(0.0) BM infiltration throughout the clinical course No | Yes Unknown 53(75.7) | 16(22.8) 1(1.5) 36(69.2) | 15(28.8) 1(2.0) 8(88.9) | 1(11.1) 0(0.0) 9(100.0) | 0(0.0) 0(0.0) Relapse No | Yes Unknown 47(67.1) | 21(30.0) 2(2.9) 34(65.4) | 17(32.7) 1(1.9) 5(55.6) | 4(44.4) 0(0.0) 8(88.9) | 0(0.0) 1(11.1) Residual recurrence No | Yes Unknown 30(42.8) | 33(47.1) 7(10.1) 23(44.2) | 26(50.0) 3(5.8) 3(33.3) | 6(66.7) 0(0.0) 4(44.4) | 1(11.2) 4(44.4) Chemotherapy No | Yes Unknown 13(18.6) | 56(80.0) 1(1.4) 5(9.6) | 47(90.4) 0(0.0) 0(0.0) | 9(100.0) 0(0.0) 8(88.9) | 0(0.0) 1(11.1) Radiotherapy No | Yes Unknown 52(74.3) | 17 (25.7) 0(0.0) 38(73.1) | 14(26.9) 0(0.0) 6(66.7) | 3(33.3) 0(0.0) 8(88.9) | 0(0.0) 1(11.1) Patient status at last follow-up Active follow-up Complete remission Death Lost to follow-up 7(10.0) 21(30.0) 20(28.6) 22(31.4) 6(11.6) 13(25.0) 18(34.6) 15(28.8) 2(22.2) 3(33.4) 2(22.2) 2(22.2) 0(0.0) 4(44.4) 0(0.0) 5(55.6) Data are presented as n (%). PNTs: Peripheral Neuroblastic Tumors; NB: neuroblastoma; GNB: ganglioneuroblastoma; GN: ganglioneuroma; BM: bone marrow. a Histological subtype presented descriptively only; genotypic association analyses were not performed due to non-estimable odds ratios. b MYCN copy number available for 26/70 patients (NB=19, GNB=1, GN=6); GNB value represents a single case (IQR not applicable). Case-control characterization Sociodemographic characteristics of PNT patients and controls are summarized in Table 3. The median age was 11 years (IQR: 7–15) in the control group and 2 years (IQR: 0–4) among patients. A statistically significant difference in age distribution was observed between groups (p < 0.001). Regarding sex distribution, the control group comprised 44 males and 52 females, whereas the case group included 37 males and 33 females. No significant difference in sex distribution was detected between groups (p = 0.371). Given the significant difference in age distribution between groups, all subsequent analyses were adjusted for age, while sex was included as a predefined covariate. Table 3 - Sociodemographic data in Peripheral Neuroblastic Tumors (PNTs) patients and controls Characteristics Controls (n=96) PNTs (n=70) p-value Age (years) 11 (7-15) 2 (0-4) <0.001* Sex Male | Female 44(45.8) | 52(54.2) 37(52.9) | 33(47.1) 0.371 P-values were calculated using the χ² test for categorical variables and the Mann–Whitney U test for continuous variables. Data were expressed as median and IQR (25-75%); Categorical variables were expressed as absolute number (n) and percentage (%); *P < 0.05 was considered statistically significant. PNTs: Peripheral Neuroblastic Tumors; Association of PARP1 , XPC , and XPA gene SNVs with PNTs susceptibility A total of 67 pediatric patients and 93 healthy children were successfully genotyped for PARP1 (rs1136410 A>G), 57 pediatric patients and 88 healthy children for XPC (rs2228000 G>A), and 69 pediatric patients and 95 healthy children for XPA (rs1800975 T>C). Differences in genotyping yield across variants were attributable to insufficient DNA quantity, DNA degradation, or depletion of available DNA during prior molecular analyses. Associations between each SNV and PNT susceptibility were evaluated using logistic regression under codominant, dominant, recessive, and overdominant genetic models. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated and all analyses were adjusted for age and sex to account for potential confounding and to ensure comparability between patients and controls. The main results are presented in Table 4. A potential association was observed between XPA rs1800975 and PNT susceptibility under the codominant and dominant models. Individuals carrying the CT genotype showed lower odds of PTN compared to TT homozygotes (OR = 0.213; 95% CI: 0.047–0.965; p = 0.045). Similarly, carriers of at least one C allele (CT+CC) exhibited reduced odds of PNT (OR = 0.228; 95% CI: 0.055–0.930; p = 0.040). However, these findings should be interpreted with caution given the limited sample size, wide confidence intervals, and multiple comparisons performed. No statistically significant associations were observed for PARP1 rs1136410 or XPC rs2228000 across the evaluated models. Genotype distributions in controls were consistent with HWE for PARP1 rs1136410 (p=0.806), XPC rs2228000 (p=0.842), and XPA rs1800975 (p=0.934). Table 4- Genetic association analysis of PARP1, XPA, and XPC SNVs in Peripheral Neuroblastic Tumors (PNTs): a case-control study. SNV Genetic model Cases Control p-value OR (95CI%) n (%) n (%) PARP1 A>G rs1136410 Codominant AA GA GG n=67 49 (73.1) 17 (25.3) 1 (1.6) n=93 64 (68.8) 26 (27.9) 3 (3.3) Reference 0.625 0.600 - 1.286 (0.470-3.518) 0.509 (0.041-6.327) Dominant AA GG+GA 49 (73.1) 18 (26.9) 64 (68.8) 29 (31.2) Reference 0.778 - 1.147 (0.442-2.977) Recessive AA+GA GG 66 (98.4) 1 (1.6) 90 (96.7) 3 (3.3) Reference 0.565 - 0.480 (0.039-5.869) Overdominant AA+GG GA 50 (74.7) 17 (25.3) 67 (72.1) 26 (27.9) Reference 0.584 - 1.323 (0.486-3.606) XPA T>C rs1800975 Codominant TT CT CC n=69 12 (17.4) 28 (40.6) 29 (42.0) n=95 8 (8.4) 39 (41.0) 48 (50.6) Reference 0.045* 0.056 - 0.213 (0.047-0.965)* 0.239 (0.055-1.038) Dominant TT CT+CC 12 (17.4) 57 (82.6) 8 (8.4) 87 (91.6) Reference 0.040* - 0.228 (0.055-0.936)* Recessive CT+TT CC 40 (58.0) 29 (42.0) 47 (49.5) 48 (50.5) Reference 0.587 - 0.791 (0.341-1.839) Overdominant CC+TT CT 41 (59.4) 28 (40.6) 56 (58.9) 39 (41.1) Reference 0.383 - 0.679 (0.285-1.620) XPC G>A rs2228000 Codominant GG AG AA n=57 39 (68.4) 14 (24.5) 4 (7.1) n=87 52 (60.2) 31 (35.2) 4 (4.6) Reference 0.216 0.992 - 0.538 (0.202-1.437) 0.990 (0.162-6.066) Dominant GG AA+AG 39 (68.4) 18 (31.6) 52 (60.2) 35 (39.8) Reference 0.275 - 0.602 (0.242-1.498) Recessive AG+GG AA 53 (92.9) 4 (7.1) 83 (95.4) 4 (4.6) Reference 0.850 - 1.188 (0.199-7.092) Overdominant AA+GG AG 43 (75.5) 14 (24.5) 56 (64.8) 31 (35.2) Reference 0.211 - 0.539 (0.204-1.422) Data are presented as absolute numbers (n) and percentages (%). Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression adjusted for age and sex. p-values were derived from the Wald test. *P < 0.05 was considered statistically significant. Stratification analysis of NER and BER genes SNVs with PNTs susceptibility Additional subgroup analyses, stratified by clinicopathological characteristics among patients diagnosed with NB, GNB, or GN, were conducted to examine whether the selected variants and their combined risk genotypes influenced susceptibility to PNTs. Adjusted OR and 95% CIs were estimated, with all analyses adjusted for age and sex to account for potential confounding. For PARP1 and XPC SNVs, codominant and recessive models yielded unreliable estimates due to the low frequency of homozygous mutant genotypes — only one individual carried the GG genotype for PARP1 and four carried the AA genotype for XPC — resulting in model instability and non-estimable odds ratios; therefore, results under these models are not reported. Genotypic distributions under the codominant model are presented descriptively for each clinicopathological parameter (Online Resource S5–S10). No statistically significant associations were identified for PARP1, XPA or XPC SNVs in the remaining models evaluated. Discussion This cross-sectional study investigated the role of germline SNVs in DNA repair genes, including PARP1 (rs1136410), XPC (rs2228000), and XPA (rs1800975), in pediatric PNTs from a Southern Brazilian population. No significant associations were observed between the evaluated genetic models for PARP1 and XPC variants and PNT susceptibility in the case–control analysis. In contrast, a potential association was observed between XPA rs1800975 and reduced susceptibility to PNTs under codominant OR=0.213 (CI 95%: 0.047-0.965; p=0.045), and dominant models OR=0.228 (CI 95%: 0.055-0.936; p=0.040). Although these findings do not support a major role for all evaluated DNA repair gene variants in PNT susceptibility, they suggest that XPA rs1800975 may act as a modifier of disease risk. In subsequent subgroup analyses stratified by clinicopathological characteristics, no statistically significant associations were identified for PARP1, XPA or XPC SNVs across the genetic models evaluated. Neuroblastoma arises from the sympathetic nervous system, where DNA repair accuracy is critical[6, 33]. Neural cells are particularly vulnerable to oxidative stress, and although the BER pathway, mediated by genes such as PARP1 , represents the primary response to these lesions, the NER pathway, involving XPA and XPC , is also essential for maintaining genomic stability [12, 34]. Impairments in DNA repair efficiency may contribute to genomic instability during neuroblast precursor development, potentially affecting tumor heterogeneity, biological behavior, and disease presentation [10] . In line with this rationale, recent systems biology approaches in high-risk neuroblastoma have highlighted a functional interplay between DNA repair pathways and chromatin remodeling processes, particularly in the context of treatment response and resistance [35]. These findings support the idea that alterations in DNA repair genes may not act in isolation, but rather as part of broader regulatory networks influencing tumor behavior. XPA and XPC are key components of the NER pathway, which primarily repairs bulky DNA damage and maintains genomic stability [12, 19]. NER operates through GG-NER and TC-NER subpathways. Defects in NER are linked to disorders such as xeroderma pigmentosum (XP), characterized by increased cancer risk and neurological issues [34, 36] . Although the functional effects of common SNVs in NER genes remain incompletely understood, evidence suggests that the XPA rs1800975 C (historically reported as A in the G>A nomenclature) allele may alter XPA expression, providing biological plausibility for its role in cancer susceptibility[23]. Consistent with previous findings in Chinese pediatric populations, our case–control analysis identified an association between the XPA rs1800975 variant and reduced PNT susceptibility. Specifically, carriers of the C allele (CT or CT+CC genotypes) exhibited lower odds of PNT diagnosis compared to TT homozygotes under codominant and dominant models. These findings align with those reported by Zhou et al. in a Chinese pediatric cohort, supporting the hypothesis that rs1800975 may reduce NB risk, potentially across populations [37]. The rs1800975 variant is located within the Kozak consensus sequence of the XPA 5'UTR, four nucleotides upstream of the translation initiation codon, a position with potential influence on translation efficiency [38]. Although direct functional studies have not demonstrated a significant effect of this variant on XPA protein levels under standard conditions, epidemiological evidence has consistently associated the variant allele (C, formerly reported as A in the G>A notation) with reduced NER capacity and altered DNA damage levels. Specifically, Wu et al. reported that individuals carrying one or two G alleles (equivalent to the T allele in the T>C nomenclature) exhibited more efficient NER capacity compared to AA homozygotes, suggesting that the variant allele may subtly impair the NER pathway without detectable changes in protein abundance [39]. The mechanistic basis of this observation remains elusive, as Butkiewicz et al. demonstrated no significant difference in XPA protein levels between GG and AA homozygous lymphoblastoid cell lines under standard conditions, and reporter assays showed no differential transcriptional activity between the two sequence variants [38] . Taken together, these findings suggest that the functional consequences of rs1800975 may be context-dependent, potentially influenced by tissue type, cellular stress conditions, or linkage disequilibrium with yet uncharacterized regulatory variants. Conversely, other studies in pediatric Chinese populations [40] did not observe a significant association between XPA rs1800975 and NB susceptibility. Such discrepancies may arise from differences in genetic background, sample size, statistical power, genetic models, or clinical heterogeneity. Taken together, these observations suggest that the influence of XPA rs1800975 on PNT risk may be context-dependent rather than universal. This underscores the importance of replication studies and population-stratified analyses[41, 42]. In contrast to XPA , no significant association was detected between the XPC rs2228000 SNV and PNT susceptibility in our case–control or stratified analyses. This result aligns with previous studies of the same variant in neuroblastoma[43] . Although XPC plays a critical role in the initial damage recognition step of NER, common variants such as rs2228000 may not exert a strong independent effect on tumor susceptibility [21]. Similarly, no significant association was detected between the PARP1 rs1136410 (A>G) SNV and PNT susceptibility in our case–control or stratified analyses. This variant is located within the catalytic domain of PARP1 , and in vitro studies show that the G allele exhibits approximately 50–60% of the enzymatic activity of the A allele [44, 45]. Despite this functional relevance, the absence of association in our cohort aligns with previous NB studies, which reported significant findings only in stratified analyses [46] . The low frequency of the homozygous variant genotype in our cohort limited statistical power. Taken together, these findings suggest that PARP1 rs1136410 is unlikely to be a major determinant of PNT susceptibility but may exert subtle, context-dependent effects. This study suggests a potential association between XPA rs1800975 and reduced susceptibility to pediatric PNTs in a Southern Brazilian population, extending the analysis to include exploratory clinicopathological correlations, for which no statistically significant associations were retained after adjustment. However, several limitations must be acknowledged. The case–control design with convenience sampling and recruitment from distinct clinical settings may introduce selection bias. Additionally, germline DNA was obtained from both peripheral blood and FFPE tumor tissue among cases, which may affect genotyping performance and could introduce potential somatic alterations despite targeting germline variants. The modest sample size, particularly within stratified subgroups, limits statistical power and increases the risk of chance findings given the evaluation of multiple genetic models. Furthermore, the lack of uniform immunohistochemical analysis across participating centers may have introduced variability in histological classification, representing an inherent limitation of the multicenter design. The absence of ancestry-informative markers also precludes complete exclusion of residual population stratification. Replication in larger, well-characterized cohorts with standardized histological protocols is warranted. Despite these limitations, our findings provide insight into the role of DNA repair gene variants in pediatric PNTs by integrating susceptibility analyses with clinical correlations. The results are consistent with a context-dependent role of common germline variants in nucleotide excision repair pathways, particularly XPA , as modest modifiers of disease risk and presentation rather than primary determinants of tumor initiation. Future multicenter studies with larger samples and pathway-based analytical strategies will be essential to clarify the combined effects of DNA repair variants and their potential relevance for risk stratification in pediatric neuroblastic tumors. Abbreviations 3’UTR Three Prime Unstranslated Region 5’UTR Five Prime Untranslated Region AHSCT Autologous Hematopoietic Stem Cell Transplantation BER Base Excision Repair BM Bone Marrow CI Confidence Interval EDTA Ethylenediaminetetraacetic Acid FFPE Formalin-Fixed Paraffin-Embedded GG-NER Global Genome Repair NER GN Ganglioneuroma GNB Ganglioneuroblastoma HWE Hardy–Weinberg equilibrium INPC International Neuroblastoma Pathology Classification IQR Interquartile Range MAF Minor Allele Frequence NB Neuroblastoma NER Nucleotide Excision Repair OR Odds Ratio PARP1 Poly(ADP-ribose)Polymerase 1 PNTs Peripheral Neuroblastic Tumors qPCR Quantitative Polymerase Chain Reaction RPA Replication Protein A SNV Single Nucleotide Variant SSBR Single Strand Break Repair TC-NER Transcription-Coupled NER XP Xeroderma Pigmentosum XPA Xeroderma Pigmentosum Complementation Group A XPC Xeroderma Pigmentosum Complementation Group C χ² Chi-square Test Declarations Data Availability: The data presented in this study is available on request from the corresponding author. Acknowledgments: This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001.The authors would like to thank all the individuals who participated in the present study: the Londrina Cancer Hospital, University Hospital of State University of Londrina, and the Pediatric Oncology Service of Hospital Pequeno Príncipe (HPP) in Curitiba, Paraná. We also thank the technicians of the Pathology sector of the Londrina Cancer Hospital, Peterson Vaz Neves, and Paola Rhaiany Lourenço Belozo, and the Pathologist Angela Gordon for their assistance in obtaining and analyzing medical records and anatomopathological examinations. Funding: This work was supported by the National Council for Scientific and Technological Development (CNPq; Grant No. 404610/2021-8 to Serpeloni), the Coordination for the Improvement of Higher Education Personnel (CAPES; Financial Code No. 01, Silva, I. M.), and INCT OncottGen. Declaration of Competing Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Credit authorship contribution statement: Beatriz Mancini Oliveira : Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing; Carlos Eduardo Coral de Oliveira : Methodology, Formal analysis, Resources, Writing – review & editing; Selene Elifio Esposito : Resources, Writing – review & editing; Nathália Ondei do Valle: Conceptualization, Methodology; Édipo Giovani França Lara : Conceptualization, Methodology; Isabely Mayara da Silva : Conceptualization, Writing – original draft, Writing – review & editing; Juliana Mara Serpeloni : Conceptualization, Resources, Writing – review & editing and Supervision, Project administration, Funding acquisition ; Roberta Losi-Guembarovski: Methodology, Resources; Tânia Hissa Anegawa : Conceptualization, Resources Conceptualization, Resources; Marla Karine Amarante : Conceptualization, Methodology, Investigation, Resources, Writing – original draft, Writing – review & editing, Visualization, Supervision. Ethnics approval: The study was approved by the Ethics Committees of the State University of Londrina (CAAE 59515722.70000.5231) and Pontifical Catholic University of Paraná (CAAE 80073124.9.0000.0020). Consent statement: Written informed consent was obtained from parents/guardians, and assent was provided by children aged 5 years or older. All participants were assigned anonymized codes to protect confidentiality. References Matthay KK, Maris JM, Schleiermacher G, et al (2016) Neuroblastoma. Nat Rev Dis Primers 2:. https://doi.org/10.1038/nrdp.2016.78 Shimada H, Ambros IM, Dehner LP, et al (1999) Terminology and morphologic criteria of neuroblastic tumors: Recommendations by the International Neuroblastoma Pathology Committee. Cancer 86:349–363. https://doi.org/10.1002/(SICI)1097-0142(19990715)86:23.0.CO;2-Y Peuchmaur M, D’Amore ESG, Joshi V V., et al (2003) Revision of the International Neuroblastoma Pathology Classification. 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Genet Mol Biol 47:e20240007. https://doi.org/10.1590/1678-4685-GMB-2024-0007 Diderich K, Alanazi M, Hoeijmakers JHJ (2011) Premature aging and cancer in nucleotide excision repair-disorders. DNA Repair (Amst) 10:772. https://doi.org/10.1016/j.dnarep.2011.04.025 Zhou C, Wang Y, He L, et al (2020) Association between NER pathway gene polymorphisms and neuroblastoma risk in an eastern Chinese population. Mol Ther Oncolytics 20:3. https://doi.org/10.1016/j.omto.2020.12.004 Butkiewicz D, Krześniak M, Vaitiekunaite R, et al (2010) A functional analysis of G23A polymorphism and the alternative splicing in the expression of the XPA gene. Cellular & Molecular Biology Letters 2010 15:4 15:611–629. https://doi.org/10.2478/S11658-010-0032-2 Wu X, Zhao H, Wei Q, et al (2003) XPA polymorphism associated with reduced lung cancer risk and a modulating effect on nucleotide excision repair capacity. Carcinogenesis 24:505–509. https://doi.org/10.1093/CARCIN/24.3.505 Tao J, Zhuo ZJ, Su M, et al (2018) XPA gene polymorphisms and risk of neuroblastoma in Chinese children: a two-center case-control study. J Cancer 9:2751. https://doi.org/10.7150/jca.25973 Cenik C, Derti A, Mellor JC, et al (2010) Genome-wide functional analysis of human 5’ untranslated region introns. Genome Biol 11:R29. https://doi.org/10.1186/gb-2010-11-3-r29 Cenik C, Chua HN, Zhang H, et al (2011) Genome Analysis Reveals Interplay between 5′UTR Introns and Nuclear mRNA Export for Secretory and Mitochondrial Genes. PLoS Genet 7:e1001366. https://doi.org/10.1371/journal.pgen.1001366 Zheng J, Zhang R, Zhu J, et al (2016) Lack of Associations between XPC Gene Polymorphisms and Neuroblastoma Susceptibility in a Chinese Population. Biomed Res Int 2016:2932049. https://doi.org/10.1155/2016/2932049 Wang XG, Wang ZQ, Tong WM, Shen Y (2007) PARP1 Val762Ala polymorphism reduces enzymatic activity. Biochem Biophys Res Commun 354:122–126. https://doi.org/10.1016/j.bbrc.2006.12.162 Qin Q, Lu J, Zhu H, et al (2014) PARP-1 Val762Ala Polymorphism and Risk of Cancer: A Meta-Analysis Based on 39 Case-Control Studies. PLoS One 9:e98022. https://doi.org/10.1371/journal.pone.0098022 Cheng J, Zhuo Z, Zhao P, et al (2019) PARP1 gene polymorphisms and neuroblastoma susceptibility in Chinese children. J Cancer 10:4159. https://doi.org/10.7150/jca.34222 Additional Declarations No competing interests reported. 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The malignant type, especially Neuroblastoma (NB), accounts for the majority of PNT cases [1].This group of tumors is characterized by marked heterogeneity, including differences in location, histopathology as classified by the Shimada System[2], biological characteristics, and prognosis[3, 4]. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA major clinical challenge lies in is the high aggressiveness of specific subtypes, as approximately 50% of NB patients present with a high-risk phenotype characterized by disseminated disease and significantly low long-term survival [1, 5, 6]. Despite intensive multidisciplinary treatment, including surgery, radiotherapy, chemotherapy, and autologous hematopoietic stem cell transplantation (AHSCT), cure rates for high-risk NB patients remain below 40%[7]. Additionally, NB is responsible for about 12% of cancer-related deaths in children under 15[1].\u003c/p\u003e\n\u003cp\u003eAlthough much is known about acquired genomic alterations that correlate with tumor phenotype (e.g., \u003cem\u003eMYCN\u003c/em\u003e amplification), there is a need to identify additional molecular markers that can predict disease behavior and improve treatment stratification [8]. In this context, the role of germline variants in DNA repair genes in pediatric cancers such as NB remains poorly understood. Maintenance of genomic stability is particularly critical in this setting, as PNTs arise, from neural precursors, a cell population especially vulnerable to DNA damage. DNA repair mechanisms, particularly Base Excision Repair (BER) and Nucleotide Excision Repair (NER), are essential for maintaining genomic integrity [9, 10]. \u0026nbsp;Defects in these pathways can lead to accumulation of DNA damage, promoting carcinogenesis[10]. Single nucleotides variants (SNVs) in genes encoding key DNA repair proteins may alter repair efficiency and influence, cancer development and progression [11].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe \u003cem\u003ePARP1\u003c/em\u003e gene encodes poly (ADP-ribose) polymerase 1 (PARP1), a key member of the PARP superfamily [9]. PARP-1 acts as an immediate sensor of DNA strand breaks [12] and plays a vital role in the BER and Single Strand Break Repair (SSBR) pathways [13\u0026ndash;15]. The protein binds to DNA breaks and immediately synthesizes poly (ADP-ribose) polymers, helping repair by recruiting essential factors, such as XRCC1, to the damage site [9]. The rs1136410 variant, located in the three prime unstranslated region (3\u0026rsquo;UTR) of the gene, has been associated with c\u0026acirc;ncer susceptibility in previous studies, including to glioma, supporting further investigation of its role in PNTs [16\u0026ndash;18]\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdditionally, the \u003cem\u003eXPC\u003c/em\u003e gene is a crucial component of the NER pathway [19]. The xeroderma pigmentosum complementation group C (XPC) protein is essential for the early damage recognition and initiation of global genome repair NER (GG-NER) [8]. Its defects are associated with an increased risk of cancer [20, 21]. The rs2228000 SNV is located in the five prime unstranslated region (5\u0026rsquo;UTR) of the gene and has been widely studied in adult cancers, such as bladder cancer [21], but its role in NB remais unclear and warrants investigation in pediatric populations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe \u003cem\u003eXPA\u003c/em\u003e gene is another essential component of the NER pathway, necessary for GG-NER and transcription-coupled repair (TC-NER) \u0026nbsp;[12, 22]. Xeroderma pigmentosum complementation group A (XPA) functions as a DNA damage recognition protein [23, 24]binding specifically to DNA lesions, likely through detection of DNA helix bending and unwinding[21]. XPA protein exists functionally as a homodimer (XPA2) and forms a complex with replication protein A (RPA) (XPA2-RPA), which increases its affinity for damaged DNA [22]. The SNV rs1800975 is located in the 5\u0026rsquo;UTR region of \u003cem\u003eXPA\u003c/em\u003e and has been linked to cancer risk in adults, such as lung, colorectal and skin cancer[25\u0026ndash;27]\u003c/p\u003e\n\u003cp\u003eFurthermore, most existing research has concentrated on populations outside South America. Investigating these variants in a Brazilian population may provide insights into population-specific genetic contributions to disease susceptibility. This study aimed to determine whether these variants are associated with PNT susceptibility and clinical presentation and disease progression PNT susceptibility and whether they influence the clinical diversity and disease progression.\u0026nbsp;\u003c/p\u003e"},{"header":"Subjects and Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy Design and Ethical Aspects\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Ethics Committees of the State University of Londrina (CAAE 59515722.70000.5231) and Pontifical Catholic University of Paran\u0026aacute; (CAAE 80073124.9.0000.0020). Written informed consent was obtained from parents/guardians, and assent was provided by children aged 5 years or older. All participants were assigned anonymized codes to protect confidentiality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case-control study enrolled 96 cancer-free children recruited from routine pediatric visits at the University Hospital of the State University of Londrina (HU-UEL), Londrina, PR, Brazil (control group) and 70 pediatric patients diagnosed with neuroblastoma (NB), ganglioneuroblastoma (GNB), or \u0026nbsp;ganglioneuroma (GN) recruited from the Pediatric Oncology Services at Hospital do C\u0026acirc;ncer de Londrina (HCL), Londrina, PR, Brazil and Hospital Pequeno Pr\u0026iacute;ncipe (HPP), Curitiba, PR, Brazil, between August 2023 and January 2025. The HCL serves as the reference oncology center for the 17th Regional Health Division of the State of Paran\u0026aacute;, southern Brazil, providing high-complexity oncological care to patients from multiple municipalities within this region [28] .\u0026nbsp;The HPP is recognized as the largest and most comprehensive pediatric hospital in Brazil [29] and has been acknowledged as one of the best pediatric hospitals in the world [30], serving patients referred from all Brazilian states. Given the rarity of PNTs, all consecutive eligible cases diagnosed during the study period were invited to participate.\u003c/p\u003e\n\u003cp\u003eTumor diagnosis was established by the attending pathologist at each participating institution. Histological classification was based on morphological criteria in accordance with the WHO Classification of Tumours [31] and the International Neuroblastoma Pathology Classification (INPC) [2], and, when available, complemented by immunohistochemical analysis [32]. Controls were selected from the same geographic region and were comparable in sex distribution. None had a prior history of cancer or other malignancy at the time of blood collection. Age and sex were included as covariates in multivariable regression models to account for potential confounding.\u003c/p\u003e\n\u003cp\u003eInclusion criteria comprised: (a) histopathological confirmation of TNPs by the attending pathologist; (b) provision of written informed consent and/or assent; and (c) availability of a peripheral blood sample or formalin-fixed paraffin-embedded (FFPE) tissue blocks. Exclusion criteria included: (a) diagnosis of other malignancies. No patients were excluded based on these criteria. Clinical, epidemiological, and pathological data were extracted from hospital records (electronic and paper-based) and are summarized in Table 2.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGenomic DNA extraction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor this purpose, four ML peripheral blood in tubes with ethylenediaminetetraacetic acid (EDTA) was collected from 13 patients at HCL. FFPE tissue blocks were obtained from 20 patients at HCL and 37 patients at HPP. Control samples consisted of peripheral blood from 96 children at HU-UEL. Blood samples were centrifuged at 3,500 rpm for 15 minutes, and buffy coat fractions were aliquoted and stored at \u0026minus;20\u0026deg;C for subsequent laboratory analysis. For transportation from Curitiba (HPP) to Londrina (UEL), samples were stored in a styrofoam container with dry ice to maintain temperatures below -80\u0026deg;C, ensuring DNA integrity. Genomic DNA was extracted using the \u003cem\u003eBIOPUR MINI SPIN PLUS extraction kit\u003c/em\u003e (Biometrix Diagn\u0026oacute;stica Ltda, Curitiba, Paran\u0026aacute;, Brazil), which employs a column-based separation method, following the manufacturer\u0026apos;s instructions with some modifications. For paraffin-embedded tissue samples, genomic DNA was extracted using the \u003cem\u003einnuPREP DNA Mini kit\u0026nbsp;\u003c/em\u003e(Analytik Jena, Jen, Germany), according to the manufacturer\u0026rsquo;s specifications. The extracted material was stored at -80\u0026deg;C until further use. The quantification of extracted genomic DNA was performed using a NanoDrop 2000c\u0026trade; spectrophotometer (ThermoScientific, Waltman, MA, USA) at 260 nm, and the 260/280 nm ratio assessed purity. The DNA concentration was standardized to 5 ng/\u0026micro;L in a final volume of 100 \u0026micro;L for genotyping analyses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnalysis of Single Nucleotide Variants in the \u003cem\u003ePARP1\u003c/em\u003e, \u003cem\u003eXPC\u003c/em\u003e and \u003cem\u003eXPA\u0026nbsp;\u003c/em\u003eGenes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVariants in the \u003cem\u003ePARP1\u0026nbsp;\u003c/em\u003eA\u0026gt;G\u003cem\u003e\u0026nbsp;\u003c/em\u003e(rs1136410), \u003cem\u003eXPA\u0026nbsp;\u003c/em\u003eT\u0026gt;C (rs1800975), and \u003cem\u003eXPC\u0026nbsp;\u003c/em\u003eG\u0026gt;A (rs2228000) genes were genotyped using quantitative polymerase chain reaction (qPCR) with TaqMan\u0026reg; probes. Validated assays were used for genotype determination (c_1515368_1_; c_482935_1_; c_16018061_10, respectively). Complete information on the variants studied is presented in Table 1. Genotyping reactions involved a final volume of 10 \u0026micro;L, containing 0.20 \u0026micro;L of allele-specific TaqMan\u0026reg; SNP 40\u0026times; probe (\u003cem\u003eApplied Biosystems, Foster City, CA, USA\u003c/em\u003e), labeled with fluorophores (VIC\u0026reg; and FAM\u0026reg;); 4.5 \u0026micro;L of TaqPath ProAmp Master Mix reagent (\u003cem\u003eApplied Biosystems, Foster City, CA, USA\u003c/em\u003e); 0.8 \u0026micro;L of Buffer (Tris-EDTA); and 4.5 \u0026micro;L of genomic DNA at 5 ng/\u0026micro;L. Thermal cycling conditions included an initial denaturation at 95 \u0026deg;C for 10 min, followed by 50 cycles of 95 \u0026deg;C for 15 s and 60 \u0026deg;C for 1 min. Amplification and allelic discrimination were conducted using the StepOnePlus\u0026trade; Real-Time PCR System (\u003cem\u003eApplied Biosystems\u003c/em\u003e). Genotype calling was performed automatically and confirmed by manual inspection of allelic discrimination plots. A random subset of samples was re-genotyped for quality control, yielding 100% concordance.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"643\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 643px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e - Genes, reference identification of single nucleotide variants (SNVs), chromosomal location, allelic exchange (region), and minor allele frequency (MAF) \u0026nbsp;in Latin American 2 (LA2), global population (Global), and in our study.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGene and alleles\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eGene name\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSNV ID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eChr. Bp/\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRegion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMAF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePathway\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGlobal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLA2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ePARP1\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eA\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003epoly(ADP-ribose) polymerase 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ers1136410\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003echr1:226367601/\u003c/p\u003e\n \u003cp\u003e3\u0026rsquo;UTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003eA=0.8349\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003eG=0.1650\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eA=0.6252\u003c/p\u003e\n \u003cp\u003eG=0.3748\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eA=0.8406\u003c/p\u003e\n \u003cp\u003eG=0.1593\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBER\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eXPC\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eG\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eXPC complex subunit, DNA damage recognition and repair factor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ers2228000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003echr3:14158387/ 5\u0026rsquo;UTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003csup\u003eb\u003c/sup\u003e\u003c/strong\u003eG=0.7580\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003csup\u003eb\u003c/sup\u003e\u003c/strong\u003eA=0.2419\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eG=0.7697\u003c/p\u003e\n \u003cp\u003eA=0.2685\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eG=0.7896\u003c/p\u003e\n \u003cp\u003eA=0.2103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNER\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eXPA\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eT\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eXPA, DNA damage recognition and repair factor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ers1800975\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003echr9:97697296/ 5\u0026rsquo;UTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003csup\u003ec\u003c/sup\u003e\u003c/strong\u003eT=0.3285\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003csup\u003ec\u003c/sup\u003e\u003c/strong\u003eC=0.6714\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eT=0.3506\u003c/p\u003e\n \u003cp\u003eC=0.6494\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eT=0.3272\u003c/p\u003e\n \u003cp\u003eC=0.6728\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNER\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 643px;\"\u003e\n \u003cp\u003eBER: Base excision repair; LA2: Latin American individuals with predominantly European and Native American ancestry; NER: Nucleotide excision repair; UTR: untranslated region. Reference:\u0026nbsp;\u003cstrong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003eALFA Project (https://www.ncbi.nlm.nih.gov/snp/rs1136410); \u003cstrong\u003e\u003csup\u003eb\u003c/sup\u003e\u003c/strong\u003eReference - \u0026nbsp;ALFA Project (https://www.ncbi.nlm.nih.gov/snp/rs2228000; \u003cstrong\u003e\u003csup\u003ec\u003c/sup\u003e\u003c/strong\u003eReference - ALFA Project (https://www.ncbi.nlm.nih.gov/snp/rs1800975).\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCategorical variables were compared between groups using the chi-square (\u0026chi;\u0026sup2;) test or Fisher\u0026rsquo;s exact test and are presented as absolute frequencies (n) and percentages (%). Continuous variables, such as age, were analyzed using the Mann\u0026ndash;Whitney U test and are reported as median and interquartile range (IQR). Genotype distributions in the control group were tested for Hardy\u0026ndash;Weinberg equilibrium (HWE) using the \u0026chi;\u0026sup2; test.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe association between SNVs and PNT susceptibility was estimated using logistic regression to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) under codominant, dominant, recessive, and overdominant inheritance models. All regression analyses were adjusted for age and sex to account for potential confounding effects. Subgroup analyses were also performed according to clinicopathological characteristics. Statistical analyses were conducted using SPSS Statistics software, version 20.0 (IBM Corp., Chicago, IL, USA). A two-tailed p-value \u0026lt; 0.05 was considered statistically significant. Given the number of comparisons performed, no formal adjustment for multiple testing was applied, and the results should be interpreted as exploratory.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eCohort characterization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 70 patients with PNTs were included, comprising 52 NB (74.3%), 9 GNB (12.9%), and 9 GN (12.9%) cases. The cohort was predominantly male (37/70, 57.8%), and the majority of NB patients presented with advanced-stage disease (III+IV, 78.4%). At last follow-up, 21 patients (30.0%) had achieved complete remission, 20 (28.6%) had died during the treatment period, and 7 (10.0%) remained under active follow-up. Missing data across clinicopathological variables primarily reflect the high rate of loss to follow-up observed in this cohort (n=22, 31.4%), as well as restricted access to paper-based or non-digitalized medical records. Detailed clinicopathological characteristics are summarized in Table 2.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"739\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 739px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2 -\u0026nbsp;\u003c/strong\u003eClinicopathological characteristics of patients with Neuroblastoma (NB), Ganglioneuroblastoma (GNB), and Ganglioneuroma (GN).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eParameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePNTs\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;n=70(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 388px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNB n=52(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGNB n=9(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGN n=9(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMale | Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e37(57.8) | 33(47.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e27(51.9) | 25(48.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6(66.6) | 3(33.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4 (44.5) | 5 (55.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at diagnosis, month\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026le;18months | \u0026gt;18months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e25(35.7) | 45(64.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e25(48.1) | 27(51.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0(0.0) | 9(100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0(0.0) | 9(100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStaging\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eI+II+IVS\u003c/p\u003e\n \u003cp\u003eIII+IV\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e19(27.1)\u003c/p\u003e\n \u003cp\u003e45(64.3)\u003c/p\u003e\n \u003cp\u003e6(8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11(21.6)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e41(78.4)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5(55.5)\u003c/p\u003e\n \u003cp\u003e4(44.5)\u003c/p\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (33.4)\u003c/p\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003cp\u003e6 (66.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDeath\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNo | Yes\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e32(45.7) | 22(31.4)\u003c/p\u003e\n \u003cp\u003e16(22.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e23(44.2) | 19(36.5)\u003c/p\u003e\n \u003cp\u003e9(19.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5(55.6) | 2(22.2)\u003c/p\u003e\n \u003cp\u003e2 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4(44.4) | 0(100.0)\u003c/p\u003e\n \u003cp\u003e5 (55.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eShimada classification\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eFavorable\u003c/p\u003e\n \u003cp\u003eUnfavorable\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e16(22.8)\u003c/p\u003e\n \u003cp\u003e11(15.8)\u003c/p\u003e\n \u003cp\u003e43(61.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9 (17.3)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;9 (17.3)\u003c/p\u003e\n \u003cp\u003e34 (65.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003cp\u003e2(22.3)\u003c/p\u003e\n \u003cp\u003e7(77.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7(77.7)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003cp\u003e2(22.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistology\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eUndifferentiated\u003c/p\u003e\n \u003cp\u003ePoorly differentiated\u003c/p\u003e\n \u003cp\u003eDiferentiated\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e16(22.8)\u003c/p\u003e\n \u003cp\u003e16(22.8)\u003c/p\u003e\n \u003cp\u003e11(15.8)\u003c/p\u003e\n \u003cp\u003e27(38.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15(28.8)\u003c/p\u003e\n \u003cp\u003e14(26.9)\u003c/p\u003e\n \u003cp\u003e8(15.5)\u003c/p\u003e\n \u003cp\u003e15(28.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1(11.1)\u003c/p\u003e\n \u003cp\u003e2(22.2)\u003c/p\u003e\n \u003cp\u003e1(11.1)\u003c/p\u003e\n \u003cp\u003e5(55.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2(22.2)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003cp\u003e7(77.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCN \u003cem\u003eMYCN\u003c/em\u003e\u003csup\u003eb\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMedian (IQR25-75)\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.510 (0.820-2.450)\u003c/p\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.850(0.820-2.900)\u003c/p\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.610(1.610-1.610)\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.145(0.730-1.410)\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetastasis at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNo | Yes\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e41(58.6) | 27(38.6)\u003c/p\u003e\n \u003cp\u003e2(2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e26(50.0) | 25(48.1)\u003c/p\u003e\n \u003cp\u003e1(1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8(88.9) | 1(11.1)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7(77.8) | 1(11.1)\u003c/p\u003e\n \u003cp\u003e1 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLate metastasis\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNo |Yes\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e45(64.3) | 24(34.3)\u003c/p\u003e\n \u003cp\u003e1(1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e30(57.7) | 21(40.4)\u003c/p\u003e\n \u003cp\u003e1(1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6(66.7) | 3(33.3)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9(100.0) | 0(0.0)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBM infiltration at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNo | Yes\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e55(78.6) | 13(18.6)\u003c/p\u003e\n \u003cp\u003e2(2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e37(71.1) | 13(25.0)\u003c/p\u003e\n \u003cp\u003e2(3.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9(100.0) | 0 (0.0)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9(100.0) | 0(0.0)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBM infiltration throughout the clinical course\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNo | Yes\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;53(75.7) | 16(22.8)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;1(1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e36(69.2) | 15(28.8)\u003c/p\u003e\n \u003cp\u003e1(2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8(88.9) | 1(11.1)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9(100.0) | 0(0.0)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRelapse\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNo | Yes\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e47(67.1) | 21(30.0)\u003c/p\u003e\n \u003cp\u003e2(2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e34(65.4) | 17(32.7)\u003c/p\u003e\n \u003cp\u003e1(1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5(55.6) | 4(44.4)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8(88.9) | 0(0.0)\u003c/p\u003e\n \u003cp\u003e1(11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResidual recurrence\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNo | Yes\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e30(42.8) | 33(47.1)\u003c/p\u003e\n \u003cp\u003e7(10.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e23(44.2) | 26(50.0)\u003c/p\u003e\n \u003cp\u003e3(5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3(33.3) | 6(66.7)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4(44.4) | 1(11.2)\u003c/p\u003e\n \u003cp\u003e4(44.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNo | Yes\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13(18.6) | 56(80.0)\u003c/p\u003e\n \u003cp\u003e1(1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5(9.6) | 47(90.4)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0(0.0) | 9(100.0)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8(88.9) | 0(0.0)\u003c/p\u003e\n \u003cp\u003e1(11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRadiotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNo | Yes\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e52(74.3) | 17 (25.7)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e38(73.1) | 14(26.9)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6(66.7) | 3(33.3)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8(88.9) | 0(0.0)\u003c/p\u003e\n \u003cp\u003e1(11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient status at last follow-up\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eActive follow-up\u003c/p\u003e\n \u003cp\u003eComplete remission\u003c/p\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003cp\u003eLost to follow-up\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7(10.0)\u003c/p\u003e\n \u003cp\u003e21(30.0)\u003c/p\u003e\n \u003cp\u003e20(28.6)\u003c/p\u003e\n \u003cp\u003e22(31.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6(11.6)\u003c/p\u003e\n \u003cp\u003e13(25.0)\u003c/p\u003e\n \u003cp\u003e18(34.6)\u003c/p\u003e\n \u003cp\u003e15(28.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2(22.2)\u003c/p\u003e\n \u003cp\u003e3(33.4)\u003c/p\u003e\n \u003cp\u003e2(22.2)\u003c/p\u003e\n \u003cp\u003e2(22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003cp\u003e4(44.4)\u003c/p\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003cp\u003e5(55.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 739px;\"\u003e\n \u003cp\u003eData are presented as n (%). PNTs: Peripheral Neuroblastic Tumors; NB: neuroblastoma; GNB: ganglioneuroblastoma; GN: ganglioneuroma; BM: bone marrow. \u003cstrong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003eHistological subtype presented descriptively only; genotypic association analyses were not performed due to non-estimable odds ratios.\u003cstrong\u003e\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u003c/strong\u003e\u003cem\u003eMYCN\u003c/em\u003e copy number available for 26/70 patients (NB=19, GNB=1, GN=6); GNB value represents a single case (IQR not applicable).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase-control characterization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSociodemographic characteristics of PNT patients and controls are summarized in Table 3. The median age was 11 years (IQR: 7\u0026ndash;15) in the control group and 2 years (IQR: 0\u0026ndash;4) among patients. A statistically significant difference in age distribution was observed between groups (p \u0026lt; 0.001). Regarding sex distribution, the control group comprised 44 males and 52 females, whereas the case group included 37 males and 33 females. No significant difference in sex distribution was detected between groups (p = 0.371). Given the significant difference in age distribution between groups, all subsequent analyses were adjusted for age, while sex was included as a predefined covariate.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 3 -\u003c/strong\u003e Sociodemographic data in\u0026nbsp;Peripheral Neuroblastic Tumors (PNTs) patients and controls\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eControls (n=96)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePNTs (n=70)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11 (7-15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (0-4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMale | Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e44(45.8) | 52(54.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e37(52.9) | 33(47.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.371\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e\n \u003cp\u003eP-values were calculated using the \u0026chi;\u0026sup2; test for categorical variables and the Mann\u0026ndash;Whitney U test for continuous variables. Data were expressed as median and IQR (25-75%); Categorical variables were expressed as absolute number (n) and percentage (%);\u0026nbsp;*P \u0026lt; 0.05 was considered statistically significant. PNTs: Peripheral Neuroblastic Tumors;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eAssociation of \u003cem\u003ePARP1\u003c/em\u003e, \u003cem\u003eXPC\u003c/em\u003e, and \u003cem\u003eXPA\u003c/em\u003e gene SNVs with PNTs susceptibility\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 67 pediatric patients and 93 healthy children were successfully genotyped for \u003cem\u003ePARP1\u0026nbsp;\u003c/em\u003e(rs1136410 A\u0026gt;G), 57 pediatric patients and 88 healthy children for \u003cem\u003eXPC\u003c/em\u003e (rs2228000 G\u0026gt;A), and 69 pediatric patients and 95 healthy children for \u003cem\u003eXPA\u003c/em\u003e (rs1800975 T\u0026gt;C). Differences in genotyping yield across variants were attributable to insufficient DNA quantity, DNA degradation, or depletion of available DNA during prior molecular analyses. Associations between each SNV and PNT susceptibility were evaluated using logistic regression under codominant, dominant, recessive, and overdominant genetic models. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated and all analyses were adjusted for age and sex to account for potential confounding and to ensure comparability between patients and controls. The main results are presented in Table 4.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA potential association was observed between \u003cem\u003eXPA\u0026nbsp;\u003c/em\u003ers1800975 and PNT susceptibility under the codominant and dominant models. Individuals carrying the CT genotype showed lower odds of PTN compared to TT homozygotes (OR = 0.213; 95% CI: 0.047\u0026ndash;0.965; p = 0.045). Similarly, carriers of at least one C allele (CT+CC) exhibited reduced odds of PNT (OR = 0.228; 95% CI: 0.055\u0026ndash;0.930; p = 0.040). However, these findings should be interpreted with caution given the limited sample size, wide confidence intervals, and multiple comparisons performed. No statistically significant associations were observed for \u003cem\u003ePARP1\u003c/em\u003e rs1136410 or \u003cem\u003eXPC\u003c/em\u003e rs2228000 across the evaluated models. Genotype distributions in controls were consistent with HWE for \u003cem\u003ePARP1\u003c/em\u003e rs1136410 (p=0.806), \u003cem\u003eXPC\u003c/em\u003e rs2228000 (p=0.842), and \u003cem\u003eXPA\u0026nbsp;\u003c/em\u003ers1800975 (p=0.934).\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"671\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 671px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 4-\u0026nbsp;\u003c/strong\u003eGenetic association analysis of \u003cem\u003ePARP1, XPA,\u0026nbsp;\u003c/em\u003eand \u003cem\u003eXPC\u0026nbsp;\u003c/em\u003eSNVs in Peripheral Neuroblastic Tumors (PNTs): a case-control study.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSNV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGenetic model\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR (95CI%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePARP1\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003eA\u0026gt;G rs1136410\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCodominant\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003cp\u003eGA\u003c/p\u003e\n \u003cp\u003eGG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003en=67\u003c/p\u003e\n \u003cp\u003e49 (73.1)\u003c/p\u003e\n \u003cp\u003e17 (25.3)\u003c/p\u003e\n \u003cp\u003e1 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003en=93\u003c/p\u003e\n \u003cp\u003e64 (68.8)\u003c/p\u003e\n \u003cp\u003e26 (27.9)\u003c/p\u003e\n \u003cp\u003e3 (3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e0.625\u003c/p\u003e\n \u003cp\u003e0.600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e1.286 (0.470-3.518)\u003c/p\u003e\n \u003cp\u003e0.509 (0.041-6.327)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDominant\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003cp\u003eGG+GA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e49 (73.1)\u003c/p\u003e\n \u003cp\u003e18 (26.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e64 (68.8)\u003c/p\u003e\n \u003cp\u003e29 (31.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e0.778\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e1.147 (0.442-2.977)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRecessive\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAA+GA\u003c/p\u003e\n \u003cp\u003eGG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e66 (98.4)\u003c/p\u003e\n \u003cp\u003e1 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e90 (96.7)\u003c/p\u003e\n \u003cp\u003e3 (3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e0.565\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e0.480 (0.039-5.869)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverdominant\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAA+GG\u003c/p\u003e\n \u003cp\u003eGA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e50 (74.7)\u003c/p\u003e\n \u003cp\u003e17 (25.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e67 (72.1)\u003c/p\u003e\n \u003cp\u003e26 (27.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e0.584\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e1.323 (0.486-3.606)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eXPA\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003eT\u0026gt;C\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ers1800975\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCodominant\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eTT\u003c/p\u003e\n \u003cp\u003eCT\u003c/p\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003en=69\u003c/p\u003e\n \u003cp\u003e12 (17.4)\u003c/p\u003e\n \u003cp\u003e28 (40.6)\u003c/p\u003e\n \u003cp\u003e29 (42.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003en=95\u003c/p\u003e\n \u003cp\u003e8 (8.4)\u003c/p\u003e\n \u003cp\u003e39 (41.0)\u003c/p\u003e\n \u003cp\u003e48 (50.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.045*\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e0.056\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.213 (0.047-0.965)*\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e0.239 (0.055-1.038)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDominant\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eTT\u003c/p\u003e\n \u003cp\u003eCT+CC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12 (17.4)\u003c/p\u003e\n \u003cp\u003e57 (82.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 (8.4)\u003c/p\u003e\n \u003cp\u003e87 (91.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.040*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.228 (0.055-0.936)*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRecessive\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCT+TT\u003c/p\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e40 (58.0)\u003c/p\u003e\n \u003cp\u003e29 (42.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e47 (49.5)\u003c/p\u003e\n \u003cp\u003e48 (50.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e0.587\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e0.791 (0.341-1.839)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverdominant\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCC+TT\u003c/p\u003e\n \u003cp\u003eCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e41 (59.4)\u003c/p\u003e\n \u003cp\u003e28 (40.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e56 (58.9)\u003c/p\u003e\n \u003cp\u003e39 (41.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e0.383\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e0.679 (0.285-1.620)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eXPC\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003eG\u0026gt;A\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003ers2228000\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCodominant\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eGG\u003c/p\u003e\n \u003cp\u003eAG\u003c/p\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003en=57\u003c/p\u003e\n \u003cp\u003e39 (68.4)\u003c/p\u003e\n \u003cp\u003e14 (24.5)\u003c/p\u003e\n \u003cp\u003e4 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003en=87\u003c/p\u003e\n \u003cp\u003e52 (60.2)\u003c/p\u003e\n \u003cp\u003e31 (35.2)\u003c/p\u003e\n \u003cp\u003e4 (4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e0.216\u003c/p\u003e\n \u003cp\u003e0.992\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e0.538 (0.202-1.437)\u003c/p\u003e\n \u003cp\u003e0.990 (0.162-6.066)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDominant\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eGG\u003c/p\u003e\n \u003cp\u003eAA+AG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e39 (68.4)\u003c/p\u003e\n \u003cp\u003e18 (31.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e52 (60.2)\u003c/p\u003e\n \u003cp\u003e35 (39.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e0.275\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e0.602 (0.242-1.498)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRecessive\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAG+GG\u003c/p\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e53 (92.9)\u003c/p\u003e\n \u003cp\u003e4 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e83 (95.4)\u003c/p\u003e\n \u003cp\u003e4 (4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e0.850\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e1.188 (0.199-7.092)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverdominant\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAA+GG\u003c/p\u003e\n \u003cp\u003eAG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e43 (75.5)\u003c/p\u003e\n \u003cp\u003e14 (24.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e56 (64.8)\u003c/p\u003e\n \u003cp\u003e31 (35.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e0.211\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e0.539 (0.204-1.422)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 671px;\"\u003e\n \u003cp\u003eData are presented as absolute numbers (n) and percentages (%). Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression adjusted for age and sex. p-values were derived from the Wald test. *P \u0026lt; 0.05 was considered statistically significant.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStratification analysis of NER and BER genes SNVs with PNTs susceptibility\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdditional subgroup analyses, stratified by clinicopathological characteristics among patients diagnosed with NB, GNB, or GN, were conducted to examine whether the selected variants and their combined risk genotypes influenced susceptibility to PNTs. Adjusted OR and 95% CIs were estimated, with all analyses adjusted for age and sex to account for potential confounding. For \u003cem\u003ePARP1\u003c/em\u003e and \u003cem\u003eXPC\u003c/em\u003e SNVs, codominant and recessive models yielded unreliable estimates due to the low frequency of homozygous mutant genotypes \u0026mdash; only one individual carried the GG genotype for \u003cem\u003ePARP1\u003c/em\u003e and four carried the AA genotype for \u003cem\u003eXPC\u003c/em\u003e \u0026mdash; resulting in model instability and non-estimable odds ratios; therefore, results under these models are not reported. Genotypic distributions under the codominant model are presented descriptively for each clinicopathological parameter (Online Resource S5\u0026ndash;S10). No statistically significant associations were identified for \u003cem\u003ePARP1, XPA\u003c/em\u003e or \u003cem\u003eXPC\u003c/em\u003e SNVs in the remaining models evaluated.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis cross-sectional study investigated the role of germline SNVs in DNA repair genes, including \u003cem\u003ePARP1\u003c/em\u003e (rs1136410), \u003cem\u003eXPC\u003c/em\u003e (rs2228000), and \u003cem\u003eXPA\u003c/em\u003e (rs1800975), in pediatric PNTs from a Southern Brazilian population. No significant associations were observed between the evaluated genetic models for \u003cem\u003ePARP1\u003c/em\u003e and \u003cem\u003eXPC\u003c/em\u003e variants and PNT susceptibility in the case\u0026ndash;control analysis. In contrast, a potential association was observed between \u003cem\u003eXPA\u0026nbsp;\u003c/em\u003ers1800975 and reduced susceptibility to PNTs under codominant OR=0.213 (CI 95%: 0.047-0.965; p=0.045), and dominant models OR=0.228 (CI 95%: 0.055-0.936; p=0.040). Although these findings do not support a major role for all evaluated DNA repair gene variants in PNT susceptibility, they suggest that \u003cem\u003eXPA\u0026nbsp;\u003c/em\u003ers1800975 may act as a modifier of disease risk.\u0026nbsp;In subsequent subgroup analyses stratified by clinicopathological characteristics, no statistically significant associations were identified for \u003cem\u003ePARP1, XPA\u003c/em\u003e or \u003cem\u003eXPC\u003c/em\u003e SNVs across the genetic models evaluated.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNeuroblastoma arises from the sympathetic nervous system, where DNA repair accuracy is critical[6, 33]. Neural cells are particularly vulnerable to oxidative stress, and although the BER pathway, mediated by genes such as \u003cem\u003ePARP1\u003c/em\u003e, represents the primary response to these lesions, the NER pathway, involving \u003cem\u003eXPA\u003c/em\u003e and \u003cem\u003eXPC\u003c/em\u003e, is also essential for maintaining genomic stability [12, 34]. Impairments in DNA repair efficiency may contribute to genomic instability during neuroblast precursor development, potentially affecting tumor heterogeneity, biological behavior, and disease presentation\u003cw:sdt docpart=\"DD23E9EF341144CE8F431DB252207AE5\" sdttag=\"MENDELEY_CITATION_v3_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\" id=\"-1780024340\"\u003e[10]\u003c/w:sdt\u003e. In line with this rationale, recent systems biology approaches in high-risk neuroblastoma have highlighted a functional interplay between DNA repair pathways and chromatin remodeling processes, particularly in the context of treatment response and resistance [35]. These findings support the idea that alterations in DNA repair genes may not act in isolation, but rather as part of broader regulatory networks influencing tumor behavior.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eXPA\u003c/em\u003e and \u003cem\u003eXPC\u003c/em\u003e are key components of the NER pathway, which primarily repairs bulky DNA damage and maintains genomic stability [12, 19]. NER operates through GG-NER and TC-NER subpathways. Defects in NER are linked to disorders such as xeroderma pigmentosum (XP), characterized by increased cancer risk and neurological issues \u003cw:sdt docpart=\"DD23E9EF341144CE8F431DB252207AE5\" sdttag=\"MENDELEY_CITATION_v3_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\" id=\"-99881692\"\u003e[34, 36]\u003c/w:sdt\u003e. Although the functional effects of common SNVs in NER genes remain incompletely understood, evidence suggests that the \u003cem\u003eXPA\u0026nbsp;\u003c/em\u003ers1800975 C (historically reported as A in the G\u0026gt;A nomenclature) allele may alter \u003cem\u003eXPA\u003c/em\u003e expression, providing biological plausibility for its role in cancer susceptibility[23].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsistent with previous findings in Chinese pediatric populations, our case\u0026ndash;control analysis identified an association between the \u003cem\u003eXPA\u0026nbsp;\u003c/em\u003ers1800975 variant and reduced PNT susceptibility. Specifically, carriers of the C allele (CT or CT+CC genotypes) exhibited lower odds of PNT diagnosis compared to TT homozygotes under codominant and dominant models. These findings align with those reported by Zhou et al. in a Chinese pediatric cohort, supporting the hypothesis that rs1800975 may reduce NB risk, potentially across populations [37]. The rs1800975 variant is located within the Kozak consensus sequence of the \u003cem\u003eXPA\u003c/em\u003e 5\u0026apos;UTR, four nucleotides upstream of the translation initiation codon, a position with potential influence on translation efficiency [38]. Although direct functional studies have not demonstrated a significant effect of this variant on XPA protein levels under standard conditions, epidemiological evidence has consistently associated the variant allele (C, formerly reported as A in the G\u0026gt;A notation) with reduced NER capacity and altered DNA damage levels.\u003c/p\u003e\n\u003cp\u003eSpecifically, Wu et al. \u0026nbsp;reported that individuals carrying one or two G alleles (equivalent to the T allele in the T\u0026gt;C nomenclature) exhibited more efficient NER capacity compared to AA homozygotes, suggesting that the variant allele may subtly impair the NER pathway without detectable changes in protein abundance [39]. The mechanistic basis of this observation remains elusive, as Butkiewicz et al. demonstrated no significant difference in XPA protein levels between GG and AA homozygous lymphoblastoid cell lines under standard conditions, and reporter assays showed no differential transcriptional activity between the two sequence variants \u003cw:sdt docpart=\"DD23E9EF341144CE8F431DB252207AE5\" sdttag=\"MENDELEY_CITATION_v3_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\" id=\"-204636258\"\u003e[38]\u003c/w:sdt\u003e. Taken together, these findings suggest that the functional consequences of rs1800975 may be context-dependent, potentially influenced by tissue type, cellular stress conditions, or linkage disequilibrium with yet uncharacterized regulatory variants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConversely, other studies in pediatric Chinese populations [40]\u0026nbsp;did not observe a significant association between \u003cem\u003eXPA\u0026nbsp;\u003c/em\u003ers1800975 and NB susceptibility. Such discrepancies may arise from differences in genetic background, sample size, statistical power, genetic models, or clinical heterogeneity. Taken together, these observations suggest that the influence of \u003cem\u003eXPA\u0026nbsp;\u003c/em\u003ers1800975 on PNT risk may be context-dependent rather than universal. This underscores the importance of replication studies and population-stratified analyses[41, 42].\u003c/p\u003e\n\u003cp\u003eIn contrast to \u003cem\u003eXPA\u003c/em\u003e, no significant association was detected between the \u003cem\u003eXPC\u0026nbsp;\u003c/em\u003ers2228000 SNV and PNT susceptibility in our case\u0026ndash;control or stratified analyses. This result aligns with previous studies of the same variant in neuroblastoma[43]\u003csup\u003e.\u0026nbsp;\u003c/sup\u003eAlthough \u003cem\u003eXPC\u003c/em\u003e plays a critical role in the initial damage recognition step of NER, common variants such as rs2228000 may not exert a strong independent effect on tumor susceptibility [21]. Similarly, no significant association was detected between the \u003cem\u003ePARP1\u0026nbsp;\u003c/em\u003ers1136410 (A\u0026gt;G) SNV and PNT susceptibility in our case\u0026ndash;control or stratified analyses. This variant is located within the catalytic domain of \u003cem\u003ePARP1\u003c/em\u003e, and in vitro studies show that the G allele exhibits approximately 50\u0026ndash;60% of the enzymatic activity of the A allele [44, 45]. Despite this functional relevance, the absence of association in our cohort aligns with previous NB studies, which reported significant findings only in stratified analyses\u003cw:sdt docpart=\"DD23E9EF341144CE8F431DB252207AE5\" sdttag=\"MENDELEY_CITATION_v3_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\" id=\"-1247724014\"\u003e[46]\u003c/w:sdt\u003e. The low frequency of the homozygous variant genotype in our cohort limited statistical power. Taken together, these findings suggest that \u003cem\u003ePARP1\u0026nbsp;\u003c/em\u003ers1136410 is unlikely to be a major determinant of PNT susceptibility but may exert subtle, context-dependent effects.\u003c/p\u003e\n\u003cp\u003eThis study suggests a potential association between XPA rs1800975 and reduced susceptibility to pediatric PNTs in a Southern Brazilian population, extending the analysis to include exploratory clinicopathological correlations, for which no statistically significant associations were retained after adjustment. However, several limitations must be acknowledged. The case\u0026ndash;control design with convenience sampling and recruitment from distinct clinical settings may introduce selection bias. Additionally, germline DNA was obtained from both peripheral blood and FFPE tumor tissue among cases, which may affect genotyping performance and could introduce potential somatic alterations despite targeting germline variants. The modest sample size, particularly within stratified subgroups, limits statistical power and increases the risk of chance findings given the evaluation of multiple genetic models. Furthermore, the lack of uniform immunohistochemical analysis across participating centers may have introduced variability in histological classification, representing an inherent limitation of the multicenter design. The absence of ancestry-informative markers also precludes complete exclusion of residual population stratification. Replication in larger, well-characterized cohorts with standardized histological protocols is warranted.\u003c/p\u003e\n\u003cp\u003eDespite these limitations, our findings provide insight into the role of DNA repair gene variants in pediatric PNTs by integrating susceptibility analyses with clinical correlations. The results are consistent with a context-dependent role of common germline variants in nucleotide excision repair pathways, particularly \u003cem\u003eXPA\u003c/em\u003e, as modest modifiers of disease risk and presentation rather than primary determinants of tumor initiation. Future multicenter studies with larger samples and pathway-based analytical strategies will be essential to clarify the combined effects of DNA repair variants and their potential relevance for risk stratification in pediatric neuroblastic tumors.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003e3\u0026rsquo;UTR\u003c/strong\u003e Three Prime Unstranslated Region\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5\u0026rsquo;UTR\u003c/strong\u003e Five Prime Untranslated Region\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAHSCT\u003c/strong\u003e Autologous Hematopoietic Stem Cell Transplantation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBER\u003c/strong\u003e Base Excision Repair\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBM\u003c/strong\u003e Bone Marrow\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCI\u003c/strong\u003e Confidence Interval\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEDTA\u003c/strong\u003e Ethylenediaminetetraacetic Acid\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFFPE\u003c/strong\u003e Formalin-Fixed Paraffin-Embedded\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGG-NER\u003c/strong\u003e Global Genome Repair NER\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGN\u003c/strong\u003e Ganglioneuroma\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGNB\u003c/strong\u003e Ganglioneuroblastoma\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHWE\u003c/strong\u003e Hardy\u0026ndash;Weinberg equilibrium\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eINPC\u003c/strong\u003e International Neuroblastoma Pathology Classification\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIQR\u003c/strong\u003e Interquartile Range\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMAF\u003c/strong\u003e Minor Allele Frequence\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNB\u003c/strong\u003e Neuroblastoma\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNER\u003c/strong\u003e Nucleotide Excision Repair\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e Odds Ratio\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePARP1\u003c/strong\u003e Poly(ADP-ribose)Polymerase 1\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePNTs\u003c/strong\u003e Peripheral Neuroblastic Tumors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eqPCR\u003c/strong\u003e Quantitative Polymerase Chain Reaction\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRPA\u003c/strong\u003e Replication Protein A\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSNV\u003c/strong\u003e Single Nucleotide Variant\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSSBR\u003c/strong\u003e Single Strand Break Repair\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTC-NER\u003c/strong\u003e Transcription-Coupled NER\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eXP\u003c/strong\u003e Xeroderma Pigmentosum\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eXPA\u003c/strong\u003e Xeroderma Pigmentosum Complementation Group A\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eXPC\u003c/strong\u003e Xeroderma Pigmentosum Complementation Group C\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026chi;\u0026sup2;\u003c/strong\u003e Chi-square Test\u003cbr clear=\"all\"\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability:\u0026nbsp;\u003c/strong\u003eThe data presented in this study is available on request from the corresponding author.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e This study was financed in part by the Coordena\u0026ccedil;\u0026atilde;o de Aperfei\u0026ccedil;oamento de Pessoal de N\u0026iacute;vel Superior \u0026ndash; Brasil (CAPES) \u0026ndash; Finance Code 001.The authors would like to thank all the individuals who participated in the present study: the Londrina Cancer Hospital, University Hospital of State University of Londrina, and the Pediatric Oncology Service of Hospital Pequeno Pr\u0026iacute;ncipe (HPP) in Curitiba, Paran\u0026aacute;. We also thank the technicians of the Pathology sector of the Londrina Cancer Hospital, Peterson Vaz Neves, and Paola Rhaiany Louren\u0026ccedil;o Belozo, and the Pathologist Angela Gordon for their assistance in obtaining and analyzing medical records and anatomopathological examinations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis work was supported by the National Council for Scientific and Technological Development (CNPq; Grant No. 404610/2021-8 to Serpeloni), the Coordination for the Improvement of Higher Education Personnel (CAPES; Financial Code No. 01, Silva, I. M.), and INCT OncottGen.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interest:\u003c/strong\u003e The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCredit authorship contribution statement: Beatriz Mancini Oliveira\u003c/strong\u003e: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing; \u003cstrong\u003eCarlos Eduardo Coral de Oliveira\u003c/strong\u003e: Methodology, Formal analysis, Resources, Writing \u0026ndash; review \u0026amp; editing;\u003cstrong\u003e\u0026nbsp;Selene Elifio Esposito\u003c/strong\u003e: Resources, Writing \u0026ndash; review \u0026amp; editing; \u003cstrong\u003eNath\u0026aacute;lia Ondei do Valle:\u003c/strong\u003e Conceptualization, Methodology; \u003cstrong\u003e\u0026Eacute;dipo Giovani Fran\u0026ccedil;a Lara\u003c/strong\u003e: Conceptualization, Methodology; \u003cstrong\u003eIsabely Mayara da Silva\u003c/strong\u003e: Conceptualization, Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing; \u003cstrong\u003eJuliana Mara Serpeloni\u003c/strong\u003e: Conceptualization, Resources, Writing \u0026ndash; review \u0026amp; editing and Supervision, Project administration, Funding acquisition\u003cstrong\u003e; Roberta Losi-Guembarovski:\u0026nbsp;\u003c/strong\u003eMethodology, Resources; \u003cstrong\u003eT\u0026acirc;nia Hissa Anegawa\u003c/strong\u003e: Conceptualization, Resources Conceptualization, Resources; \u003cstrong\u003eMarla Karine Amarante\u003c/strong\u003e: Conceptualization, Methodology, Investigation, Resources, Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing, Visualization, Supervision.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthnics approval:\u003c/strong\u003e The study was approved by the Ethics Committees of the State University of Londrina (CAAE 59515722.70000.5231) and Pontifical Catholic University of Paran\u0026aacute; (CAAE 80073124.9.0000.0020).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent statement:\u0026nbsp;\u003c/strong\u003eWritten informed consent was obtained from parents/guardians, and assent was provided by children aged 5 years or older. All participants were assigned anonymized codes to protect confidentiality.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMatthay KK, Maris JM, Schleiermacher G, et al (2016) Neuroblastoma. Nat Rev Dis Primers 2:. https://doi.org/10.1038/nrdp.2016.78\u003c/li\u003e\n\u003cli\u003eShimada H, Ambros IM, Dehner LP, et al (1999) Terminology and morphologic criteria of neuroblastic tumors: Recommendations by the International Neuroblastoma Pathology Committee. Cancer 86:349\u0026ndash;363. https://doi.org/10.1002/(SICI)1097-0142(19990715)86:2\u0026lt;349::AID-CNCR20\u0026gt;3.0.CO;2-Y\u003c/li\u003e\n\u003cli\u003ePeuchmaur M, D\u0026rsquo;Amore ESG, Joshi V V., et al (2003) Revision of the International Neuroblastoma Pathology Classification. Cancer 98:2274\u0026ndash;2281. https://doi.org/10.1002/cncr.11773\u003c/li\u003e\n\u003cli\u003eShimada H, Umehara S, Monobe Y, et al (2001) International Neuroblastoma Pathology Classification for Prognostic Evaluation of Patients with Peripheral Neuroblastic Tumors A Report from the Children\u0026rsquo;s Cancer Group. https://doi.org/10.1002/1097-0142(20011101)92:9\u0026lt;2451::AID-CNCR1595\u0026gt;3.0.CO;2-S\u003c/li\u003e\n\u003cli\u003eBerthold F, Boos J, Burdach S, et al (2005) Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: A randomised controlled trial. Lancet Oncology 6:649\u0026ndash;658. https://doi.org/10.1016/S1470-2045(05)70291-6\u003c/li\u003e\n\u003cli\u003eMaris JM, Hogarty MD, Bagatell R, Cohn SL (2007) Neuroblastoma. 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J Cancer 10:4159. https://doi.org/10.7150/jca.34222\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"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":"molecular-biology-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mole","sideBox":"Learn more about [Molecular Biology Reports](https://www.springer.com/journal/11033)","snPcode":"11033","submissionUrl":"https://submission.nature.com/new-submission/11033/3","title":"Molecular Biology Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"peripheral neuroblastic tumors, neuroblastoma, DNA repair, XPA, PARP1, XPC, genetic susceptibility, biomarkers","lastPublishedDoi":"10.21203/rs.3.rs-9419277/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9419277/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Peripheral neuroblastic tumors (PNTs) are embryonal pediatric neoplasms characterized by marked clinical heterogeneity. Germline variation in DNA repair genes may influence genomic stability and modulate tumor susceptibility and disease phenotype. We evaluated the association of single nucleotide variants (SNVs) in \u003cem\u003ePARP1\u003c/em\u003e(rs1136410), \u003cem\u003eXPC\u003c/em\u003e (rs2228000), and \u003cem\u003eXPA\u003c/em\u003e (rs1800975) with PNT risk and clinicopathological characteristics in a pediatric population from Southern Brazil.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods and Results: \u003c/strong\u003eA case-control study was conducted including 70 cases diagnosed with neuroblastoma (NB), ganglioneuroblastoma (GNB), or ganglioneuroma (GN) at two oncology referral centers in Paraná, Brazil, and 96 controls. Genotyping was performed using validated TaqMan allelic discrimination assays, with sample sizes varying per gene due to DNA integrity constraints. Associations with disease susceptibility and clinicopathological variables were assessed using logistic regression adjusted for age and sex. No significant associations were observed for \u003cem\u003ePARP1\u003c/em\u003ers1136410 or \u003cem\u003eXPC\u003c/em\u003e rs2228000 under any genetic model evaluated. The \u003cem\u003eXPA\u003c/em\u003ers1800975 C allele was associated with reduced PNT susceptibility under codominant (OR=0.213; 95%CI 0.047–0.965; p=0.045) and dominant models (OR=0.228; 95%CI 0.055–0.936; p=0.040). No statistically significant associations were retained for any SNV in stratified analyses of clinicopathological variables after adjustment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e These findings suggest that \u003cem\u003eXPA\u003c/em\u003ers1800975 may act as a modest modifier of PNT susceptibility in a Southern Brazilian pediatric population, while \u003cem\u003ePARP1\u003c/em\u003e rs1136410 and \u003cem\u003eXPC\u003c/em\u003ers2228000 were not associated with disease risk. Replication in larger, population-stratified cohorts is warranted to clarify the role of DNA repair gene variants in pediatric neuroblastic tumor biology.\u003c/p\u003e","manuscriptTitle":"Germline Variants in DNA Repair Genes and Susceptibility to Pediatric Peripheral Neuroblastic Tumors: A Case-Controle Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-20 04:06:29","doi":"10.21203/rs.3.rs-9419277/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-19T15:13:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-16T13:31:58+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-16T13:31:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Biology Reports","date":"2026-04-14T19:56:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-biology-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mole","sideBox":"Learn more about [Molecular Biology Reports](https://www.springer.com/journal/11033)","snPcode":"11033","submissionUrl":"https://submission.nature.com/new-submission/11033/3","title":"Molecular Biology Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b257a991-0e57-4b31-9cec-8e478e87c9ba","owner":[],"postedDate":"April 20th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-30T13:53:19+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-20 04:06:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9419277","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9419277","identity":"rs-9419277","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}