==== Front J Cancer J Cancer jca Journal of Cancer 1837-9664 Ivyspring International Publisher Sydney 10.7150/jca.49925 jcav12p0264 Research Paper The Association of Polymorphisms in Base Excision Repair Genes with Ovarian Cancer Susceptibility in Chinese Women: A Two-Center Case-Control Study Zhang Mingyao 1# Zhao Zhiguang 2# Chen Sailing 1 Liang Zongwen 1 Zhu Jiawei 1 Zhao Manman 1 Xu Chaoyi 1 He Jing 3 Duan Ping 1✉ Zhang Anqi 1✉ 1 Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China. 2 Department of Pathology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China. 3 Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China. ✉ Corresponding authors: Anqi Zhang, E-mail: angel19911014@gmail.com & Ping Duan, E-mail: dppddpp@wmu.edu.cn. Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109 West Xueyuan Road, Wenzhou 325027, Zhejiang, China. Tel and Fax: (0577)88816381. #These authors contributed equally to the work. Competing Interests: The authors have declared that no competing interest exists. 2021 1 1 2021 12 1 264269 25 6 2020 11 10 2020 © The author(s) 2021 This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Base excision repair (BER) acts upon the most important mechanism of the DNA repair system, protecting DNA stability and integrity from the mutagenic and cytotoxic effects. Multiple researches have indicated that single-nucleotide polymorphisms (SNPs) in the BER-related gene may be associated with the susceptibility of ovarian cancer. However, the results are controversial. In this two-center case-control study, 19 potentially functional SNPs in six BER-related genes (hOGG1, APE1, PARP1, FEN1, LIG3 and XRCC1) was genotyped in 196 ovarian cancer cases and 272 cancer-free controls. And, their associations with ovarian cancer risk were assessed by unconditional logistic regression analyses. We found that PARP1 rs8679 and hOGG1 rs293795 polymorphisms were associated with a decreased risk of ovarian cancer under dominant model (adjusted OR=0.39, 95% CI=0.17-0.90, P=0.026; and adjusted OR=0.36, 95% CI=0.13-0.99, P=0.049, respectively). Stratification analysis demonstrated that this association was more pronounced in the subgroups of lower BMI and patients with early menarche and serous carcinoma. Moreover, LIG3 rs4796030 AA/AC variant genotypes performed an increased risk of ovarian cancer under recessive model (adjusted OR=1.54, 95% CI=1.01-2.35, P=0.046), especially in the subgroups of higher BMI, early clinic stage and the carcinoma at the left. These results suggested that PARP1, hOGG1 and LIG3 polymorphisms might impact on the risk of ovarian cancer. However, more researches with larger and different ethnic populations are warranted to support our findings. BER DNA repair ovarian cancer susceptibility polymorphism ==== Body Introduction Ovarian cancer is the main cause of death in gynecological malignancy according to global cancer statistics in 2018, with an estimated 184,799 deaths worldwide 1. The common risk factors of that result in extremely poor 5-year survival, such as asymptomatic characteristics and the lack of early detection strategies, have become an immediate problem to be solved for ovarian cancer 2, 3. Thus, ovarian cancer remains a great burden and challenge for the affected family and public health. Numerous studies have indicated that the risk of ovarian cancer was related to BRCA1 and BRCA2 genes. Marc D. et al. 4 found that BRCA1/2 mutations may ultimately impact ovarian cancer mortality. Adrianna et al. 5 demonstrated significantly increased APC rs11954856 and rs351771 frequencies in Polish women with ovarian cancer. However, several genetic studies published recently had suggested that the risk of ovarian cancer was related to the mutations and polymorphic variants in DNA repair genes 6, 7. DNA repair mechanism mainly include direct repair, base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR) 8. The primary DNA damage repair pathway, BER, is responsible for the modification of the most common forms of DNA damage, such as spontaneous hydrolytic, oxidative and alkylative lesions and single-strand breaks 9. Although considerable genetic studies demonstrated that the deficiency of BER related genes would influence on ovarian cancer risk, the real relationship between both of them remained controversial 10. BER processes can be divided into the following three basic steps: damage recognition/strand scission, gap tailoring and gap filling/nick ligation 11. Based on different types of base lesions, either of two subways (short patch or long patch BER) will be initiated by corresponding lesion-specific DNA glycosylase 12. 8-oxoguanine glycosylase (hOGG1) acts as one of the most important bifunctional glycosylases, which cannot only excise the substrate base but also incises DNA 3' to the damage site via an intrinsic AP lyase activity 13. Meanwhile, apurinic endonuclease 1 (APE1) removes the resulting 3'-obstructive termini and prepares for next polymerization and/or nick ligation 14. Differing from the classical initial step, however, the single-strand break repair (SSBR) depends on poly (ADP-ribose) polymerase 1 (PARP1) to recognize the damage and recruit other protein to the damage site 15. In addition, flap endonuclease (FEN1) was also included in our study for its gap-tailoring properties in the DNA ends 16. DNA ligase 1 (LIG1) and the complex of DNA ligase 3 (LIG3)/X-ray repair cross-complementing 1 (XRCC1) exhibit similar performance of nick ligation, but we only selected LIG3/XRCC1 as the investigated biomarker for its unique character of collecting proteins at the damaged site 17, 18. In the current study, we analyze the associations between 19 SNPs of six BER-related genes (hOGG1, APE1, PARP1, FEN1, LIG3 and XRCC1) and ovarian cancer risk by genotyping method in 196 patients and 272 controls. Materials and Methods Patients and controls In this hospital-based case-control study, 196 ovarian cancer patients were newly diagnosed and histopathologically confirmed in two different institutions of the Second Affiliated Hospital and Yuying Children's Hospital and the First Affiliated Hospital of Wenzhou Medical University (WMU) from February 2007 to March 2018. Additionally, we selected 272 cancer-free women who participated in the routine physical examination of the Second Affiliated Hospital and Yuying Children's Hospital of WMU. All of them were frequency-matched to cases on age (± 2 years) and race/ethnicity, and reconfirmed without any personal tumor history or family tumor history. All people included in the present research had signed a written informed consent. The demographic data and environmental exposure factors, such as age, BMI, menarche, menopause, number of pregnancies, were collected from each participant. Clinical and pathological information were further extracted from the patients' electronical database, including pathologic classification (WHO 2014), histology grade, FIGO stage (International Federation of Gynecology and Obstetrics), tumor size (the largest tumor diameter of the primary tumor) and anatomic neoplasm subdivision. However, the patients who were diagnosed without histology grade would be categorized as a single group of “undermined”. And, some patients with some rare pathological classification were included in the “others” pathological group. The research was approved by the Second Affiliated Hospital and Yuying Children's Hospital of WMU. Our study was conducted following the Declaration of Helsinki, and participants or guardians were required to sign informed consent forms. Blood samples were obtained from cases before receiving radiotherapy or chemotherapy. SNP selection and genotyping The SNPs were selected from the NCBI dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP) and the International HapMap Project database (http://hapmap.ncbi.nlm.nih.gov/) based on the following criteria: (1) located at the coding sequence, the 5' near gene, 5'-untranslated region (UTR), 3' UTR and 3' near gene, (2) minor allele frequency (MAF) of at least 5 % in Chinese populations reported in HapMap, (3) low linkage disequilibrium (LD) between SNPs with an r2 threshold of < 0.8, and (4) predicted SNPs potential function using the SNP function prediction (FuncPred) software (https://snpinfo.niehs.nih.gov/snpinfo/snpfunc.html). As a result, a full list containing 19 selected SNPs was presented with potential function in Supplemental Table S1 19. For all cases, the DNA genomic was extracted from paraffin-embedded tissue using TIANquick FFPE DNA Kit (Qiagen Inc., Valencia, CA), while the DNA genomic of all controls were extracted from the peripheral blood specimens using the TIANamp Blood DNA Kit (TianGen Biotech Co. Ltd.). DNA purity and concentration were measured by a UV spectrophotometer (Nano Drop Technologies, Inc., Wilmington, DE). According to standard protocols, the genotyping of 19 selected SNPs was performed with a TaqMan real-time PCR assay in ABI Prism 7900HT genetic detection system (Applied Biosystems Inc., USA) 20-22. To confirm the accuracy of the genotyping, 5% samples were randomly selected as positive controls (repeat samples) and negative controls (without DNA template). As a result, the genotyping success rate reached 96.8%, and the results of duplicated samples were 100% concordant. Statistical analysis All statistical tests were performed by SAS software (Version 9.4; SAS Institute, Cary, NC, USA). Differences in demographic (e.g., age and BMI) and other covariates (e.g., menarche, menopause and number of pregnancies status) between patients and controls were evaluated by Pearson's χ2 test. To assess the associations of these 19 SNPs with ovarian cancer risk, the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for dominant (AB+BB vs. AA) and recessive models (BB vs. AB+AA) by unconditional logistic regression analyses. A and B respectively represent different alleles (wild and mutant) at this location. Additionally, stratification analysis was performed to further evaluate the significant associations existed in which demographic or clinic covariates groups. Deviation from Hardy-Weinberg Equilibrium (HWE) in the controls was assessed by a goodness-of-fit χ2 test. All P value was two-sided with a significant level < 0.05. Results Population characteristics In the current study, we enrolled 196 ovarian cancer patients with an average age of 50.01 ± 12.51 years and 272 cancer-free controls with an average age of 50.48 ± 11.98 years. The demographic and clinical characteristics of all participants were shown in Supplemental Table S2. There were no significant differences between cases and controls in age (P=0.570), BMI (P=0.947), menarche (P=0.072), menopause (P=0.421) and number of pregnancies (P=0.448). To discuss the pathological classification, 132 (67.4%), 27 (13.8%) and 15 (7.7%) cases were subdivided into serous, mucinous and clear cell carcinoma, respectively, while 22 (11.2%) cases were included into “others” because of the limited availability of tumor samples. Regarding anatomic neoplasm subdivision, 27 (13.8%), 74 (37.8%) and 95 (48.5%) ovarian cancers occurred in the left, right and both sides, respectively. In term of tumor size, 27 (13.8%) patients reported with a tumor of < 5cm, 74 (37.8%) with a tumor of 5-10 cm and 95 (48.5%) with a tumor of >10cm. According to the FIGO stage, 96 (49.0%) and 100 (51.0%) cases distributed into the stage of I+II and III+V, respectively. Moreover, we classified all patients into four different histological grades, 14 (7.1%) in G1, 20 (10.2%) in G2, 114 (58.2%) in G3+G4 and 17 (8.7%) in borderline tumor, but an exception of 31 cases (15.8%) were into the groups of “undetermined” due to the lack of information. Association between the SNPs of BER-related genes and risk of ovarian cancer Genotype distributions of these 19 SNPs are shown in Table 1. All these genotype distributions among the controls conformed to the HWE except FEN1 rs174538. Nevertheless, our results verified PARP rs8679 and hOGG1 rs293795 GG/AG were associated with the decreased risk of ovarian cancer under dominant model (adjusted OR=0.39, 95% CI=0.17-0.90, P=0.026; adjusted OR=0.36, 95% CI=0.13-0.99, P=0.049, respectively). And, the increased risk of ovarian cancer was observed in the participants who carried rs4796030 AA genotype compared with the genotype AC/CC (adjusted OR=1.54, 95% CI=1.01-2.35, P=0.046) under recessive model. However, other genetic associations with ovarian cancer risk were not discovered in the present study. Stratification analysis In order to further explore these significant genetic associations existing in which kinds of ovarian cancer patients, we performed a stratification analysis by age, BMI, menarche, menopause and number of pregnancies status, as well as some clinic-related factors like pathologic classification, histology grade, FIGO stage, tumor size and anatomic neoplasm subdivision (Table 2). Compared to the PARP1 rs8679 AA genotype, the protective effect of AG/GG genotypes were more predominant in the patients with BMI < 24 (adjusted OR=0.27, 95% CI=0.08-0.96, P=0.043), menarche age ≤ 14 (adjusted OR=0.09, 95% CI=0.01-0.65, P=0.017) and serous carcinoma (adjusted OR=0.36, 95% CI=0.14-0.98, P=0.045). Moreover, we found the LIG3 rs4796030 CC genotype carriers further increased the risk of ovarian cancer in the groups of BMI ≥ 24 (adjusted OR=2.28, 95% CI=1.14-4.58, P=0.021), clinical stages III/IV (adjusted OR=1.93, 95% CI=1.14-3.26, P=0.015) and tumor at the left (adjusted OR=2.33, 95% CI=1.34-4.06, P=0.003) when compared with the AA/AC genotype carriers. Unfortunately, stratification analysis could not explain the protective effect of hOGG1 rs293795 polymorphism on which subgroup of ovarian cancer patients. Discussion The evidence derived from numerous studies had testified the important role of BER in the prevention of mutation accumulation 23, 24. According to different base lesions, BER can trigger corresponding subways and assemble a series of repair complex at the site of DNA lesions 25. Compared with other DNA repair system, the core components of BER are quite conserved across most species. As is mentioned above, the whole repair processes are simplified as three distinct phases, and the completion of each step is based on the scaffold protein of XRCC1/LIG3 and PARP1 26. hOGG1, one of the most important bi-functional glycosylases, is initiated by some oxidative base lesions 13. The study reported by Xie et al. found that the hOGG1 deficiency animals would increase tumor predisposition, especially for the lung and ovarian tumors and lymphomas 27. Similarly, with the increasing of spontaneous mutant frequencies in the APE1 heterozygous mice, the organism also suffered many deleterious effects brought by oxidative stress, including cancer 28, 29. Although FEN1 was the only one endonuclease included in the present study, its potential role in cancer development was fully demonstrated by a heterozygous animal model 30. Numerous investigations have tried to uncover the genetic association of ovarian cancer in these six genes; however, no firm conclusions could be drawn from them. For example, hOGG1 rs1052133 as one of the hottest spots in the recent years has been researched extensively in ovarian cancer. According to the studies of Michalska and Chen, hOGG1 rs1052133 C>G polymorphism was considered as an unfavorable factor for the susceptibility of ovarian cancer 31, 32, but a totally different result was discovered in our research. Arc and reached the same conclusion with us and suggested that there was no association between both of them 33. Likewise, a negative association was observed between XRCC1 rs25487 G>A and ovarian cancer risk in Serbian women 34, while this finding was unable to repeat in another study by Khokhrin and ours 35. In fact, these contradictory conclusions were caused by several factors, of which the relatively limited sample size and different genetic backgrounds a probably the most critical reasons. In this current hospital-based case-control study, we not only explored the impact of 19 potentially functional SNPs in six BER-related genes on ovarian cancer risk, but also conducted an analysis of gene-environmental interactions in a certain number of cases and controls from two different institutions. The genotyping results indicated that the PARP1 rs8679 and hOGG1 rs293795 A>G polymorphisms were associated with the decreased ovarian cancer risk under a dominant model, while LIG3 rs4796030 A>C polymorphism with an increased ovarian cancer risk under a recessive model. Additionally, we noticed that the protective effect of PARP1 rs8679 A>G polymorphism was more pronounced among the groups of BMI < 24, menarche age ≤ 14 and serous carcinoma. Moreover, the negative effect of LIG3 rs4796030 A>C polymorphism significantly associated with the patients in the groups of BMI ≥ 24, clinical stages III/IV and tumor at the left. The preliminary results obtained here indicated that compared with patients of BMI ≥ 24, patients of BMI < 24 had a more prominent protective effect of genetic variation, and their negative effects were relatively small. These results showed that healthy lifestyle also played an important role in the development of cancer. The role of genetic variation was also related to the pathological type and clinical stage of cancer. Although we found two novel related SNPs associating with the risk of ovarian cancer, some inherent limitations still should be listed to discussion. Firstly, the limited number of cases and controls would cause a deficiency of statistical power to some extent. Secondly, many relative risk factors of ovarian cancer, such as oral contraceptive, CA125 and breast feeding, are not fully considered due to lack of individual information. Thirdly, only 19 SNPs of six BER-related genes were investigated in the present study, which was insufficiently to explain the biological relationship of BER with the risk of ovarian cancer. Fourthly, we noticed that the genotype frequencies of FEN1 rs174538 G>A deviate from HWE, which indicates that our research may exist the problem sampling bias to some extent. Finally, these new findings in our research were not confirmed in vitro and in vivo experiences, and the survival analysis for SNPs was not explored further. In conclusion, our study suggested that the PARP1 and hOGG1 polymorphisms might correlate to ovarian cancer susceptibility. However, more comprehensive studies with larger independent cohorts should be provided to verify the relationship between these significant genetic variations in PARP1 and hOGG1 gens and ovarian cancer risk. Supplementary Material Supplementary tables. Click here for additional data file. This study was supported by grants from Lin He's New Medicine and Clinical Translation Academician Workstation Research Fund (17331204), Zhejiang Provincial Medical and Health Science and Technology plan (2018ZD009), the Major Science and Technology Special Project of Wenzhou Science and Technology Bureau (ZY2020009) and Le Fund (KH-2020-LJJ-030). Table 1 Association between polymorphisms in base excision repair pathway gene and ovarian cancer risk Gene SNP Allele Case (N=196) Control (N=272) Adjusted ORa Pa Adjusted ORb Pb HWE A B AA AB BB AA AB BB (95% CI) (95% CI) PARP1 rs2666428 T C 129 49 7 171 87 13 0.73 (0.49-1.09) 0.126 0.80 (0.31-2.05) 0.637 0.653 PARP1 rs8679 A G 177 8 0 241 26 1 0.39 (0.17-0.90) 0.026 - - 0.740 hOGG1 rs1052133 G C 78 87 29 110 115 47 1.03 (0.71-1.51) 0.870 0.84 (0.50-1.39) 0.486 0.079 hOGG1 rs159153 T C 160 32 1 221 46 5 0.95 (0.58-1.54) 0.823 0.28 (0.03-2.46) 0.252 0.164 hOGG1 rs293795 A G 183 5 0 253 18 1 0.36 (0.13-0.99) 0.049 - - 0.279 FEN1 rs174538 G A 45 143 0 73 199 0 1.17 (0.76-1.79) 0.484 - - <0.001 FEN1 rs4246215 G T 46 96 52 74 135 63 1.22 (0.80-1.88) 0.361 1.26 (0.82-1.93) 0.296 0.925 APEX1 rs1130409 T G 64 100 29 91 123 54 1.05 (0.71-1.57) 0.801 0.72 (0.43-1.18) 0.190 0.293 APEX1 rs1760944 T G 65 89 38 104 122 46 1.18 (0.80-1.74) 0.412 1.18 (0.73-1.91) 0.501 0.321 APEX1 rs3136817 T C 158 33 3 224 43 5 1.08 (0.67-1.75) 0.754 0.85 (0.20-3.64) 0.822 0.095 LIG3 rs1052536 C T 92 85 15 131 116 21 1.04 (0.71-1.51) 0.847 1.02 (0.51-2.05) 0.958 0.502 LIG3 rs3744356 C T 188 3 1 261 10 0 0.56 (0.17-1.82) 0.331 - - 0.757 LIG3 rs4796030 A C 77 55 61 88 117 62 0.73 (0.49-1.08) 0.112 1.54 (1.01-2.35) 0.046 0.060 XRCC1 rs1799782 G A 99 75 19 146 105 18 1.11 (0.77-1.62) 0.570 1.53 (0.78-3.01) 0.218 0.881 XRCC1 rs25487 C T 89 83 21 146 97 24 1.43 (0.98-2.08) 0.063 1.31 (0.70-2.45) 0.395 0.182 XRCC1 rs25489 G A 139 50 5 215 50 7 1.48 (0.96-2.28) 0.074 0.99 (0.31-3.21) 0.985 0.059 XRCC1 rs2682585 G A 146 44 3 205 60 3 1.06 (0.68-1.64) 0.803 1.49 (0.29-7.62) 0.634 0.547 XRCC1 rs3810378 G C 102 70 23 147 101 24 1.10 (0.76-1.60) 0.624 1.45(0.79-2.66) 0.236 0.273 XRCC1 rs915927 T C 159 33 1 213 56 3 0.76 (0.47-1.22) 0.261 0.49 (0.05-4.87) 0.543 0.749 OR, odds ratio; CI, confidence interval. HWE, Hardy-Weinberg equilibrium. The results were in bold, if the 95% CI excluded 1 or P-values less than 0.05. a: Adjusted for age, BMI, menarche, menopause, number of pregnancies for dominant model. b: Adjusted for age, BMI, menarche, menopause, number of pregnancies for recessive model. Table 2 Stratification analysis of base excision repair pathway gene variant genotypes with ovarian cancer risk Variables PARP1 rs8679 (cases/controls) AOR (95% CI)a Pa hOGG1 rs293795 (cases/controls) AOR (95% CI)a Pa LIG3 rs4796030 (cases/controls) AOR (95% CI)a Pa AA AG/GG AA AG/GG AA/AC CC Age < 51 86/112 5/13 0.50 (0.17-1.46) 0.205 88/116 3/10 0.40 (0.11-1.48) 0.168 70/100 25/24 1.49 (0.79-2.82) 0.222 ≥ 51 91/129 3/14 0.30 (0.09-1.09) 0.067 95/137 2/9 0.32 (0.07-1.52) 0.151 62/105 36/38 1.60 (0.92-2.79) 0.094 BMI < 24 119/162 3/15 0.27 (0.08-0.96) 0.043 122/167 3/14 0.29 (0.08-1.04) 0.058 94/135 35/41 1.23 (0.73-2.07) 0.445 ≥ 24 58/79 5/12 0.57 (0.19-1.70) 0.312 61/86 2/5 0.56 (0.11-3.00) 0.502 38/70 26/21 2.28 (1.14-4.58) 0.021 Menarche ≤ 14 95/145 1/18 0.09 (0.01-0.65) 0.017 97/156 1/11 0.15 (0.02-1.15) 0.068 73/129 28/34 1.46 (0.82-2.59) 0.202 > 14 82/96 7/9 0.91 (0.33-2.55) 0.859 86/97 4/8 0.56 (0.16-1.94) 0.363 59/76 33/28 1.52 (0.83-2.79) 0.178 Menopause no 87/110 4/12 0.42 (0.13-1.35) 0.146 90/115 2/8 0.32 (0.07-1.54) 0.155 70/100 25/21 1.70 (0.88-3.28) 0.112 yes 90/131 4/15 0.39 (0.13-1.21) 0.102 93/138 3/11 0.41 (0.11-1.49) 0.174 62/105 36/41 1.49 (0.86-2.57) 0.155 Number of pregnancies ≤ 1 63/78 2/9 0.28 (0.06-1.32) 0.107 66/84 0/4 - - 50/69 19/17 1.54 (0.73-3.26) 0.257 > 1 114/163 6/18 0.48 (0.18-1.24) 0.128 117/169 5/15 0.48 (0.17-1.36) 0.168 82/136 42/45 1.55 (0.94-2.56) 0.088 Clinical stages I/II 87/241 3/27 0.30 (0.09-1.03) 0.056 90/253 2/19 0.33(0.07-1.44) 0.140 63/205 33/62 1.93 (1.14-3.26) 0.015 III/IV 90/241 5/27 0.52 (0.19-1.41) 0.197 93/253 3/19 0.40 (0.11-1.39) 0.147 69/205 28/62 1.27(0.74-2.17) 0.387 Pathology Serous carcinoma 119/241 5/27 0.36 (0.14-0.98) 0.045 121/253 4/19 0.41 (0.13-1.25) 0.118 87/205 43/62 1.58 (0.98-2.53) 0.058 Mucinous carcinoma 25/241 0/27 - - 26/253 0/19 - - 16/205 10/62 2.34 (0.98-5.57) 0.055 Clear cell carcinoma 15/241 0/27 - - 15/253 0/19 - - 12/205 3/62 0.94 (0.25-3.52) 0.922 Others 18/241 3/27 1.52 (0.41-5.67) 0.533 21/253 1/19 0.65 (0.08-5.18) 0.680 17/205 5/62 0.95 (0.33-2.74) 0.922 Anatomic neoplasm subdivision Left 67/241 5/27 0.67 (0.25-1.81) 0.425 68/253 4/19 0.81 (0.26-2.50) 0.718 43/205 30/62 2.33 (1.34-4.06) 0.003 Right 49/241 0/27 - - 51/253 0/19 - - 43/205 9/62 0.75(0.34-1.67) 0.488 Bilateral 61/241 3/27 0.45 (0.13-1.54) 0.201 64/253 1/19 0.17 (0.02-1.37) 0.097 46/205 22/62 1.49 (0.82-2.72) 0.189 Tumor size < 5 cm 23/241 1/27 0.41 (0.05-3.17) 0.392 25/253 0/19 - - 20/205 7/62 1.15 (0.45-2.91) 0.770 5-10 cm 69/241 3/27 0.39 (0.11-1.33) 0.132 68/253 4/19 0.78 (0.25-2.43) 0.672 49/205 24/62 1.58 (0.89-2.83) 0.119 > 10 cm 85/241 4/27 0.42 (0.14-1.25) 0.121 90/253 1/19 0.15 (0.02-1.16) 0.069 63/205 30/62 1.62 (0.96-2.74) 0.074 Grade G1 13/241 0/27 - - 14/253 0/19 - - 9/205 5/62 1.20 (0.68-7.10) 0.189 G2 18/241 1/27 0.54 (0.07-4.29) 0.558 20/253 0/19 - - 11/205 9/62 2.61 (1.00-6.84) 0.051 G3&G4 100/241 6/27 0.55 (0.22-1.39) 0.206 104/253 4/19 0.47 (0.15-1.44) 0.187 81/205 30/62 1.14(0.68-1.91) 0.618 Borderline tumor 17/241 0/27 - - 16/253 0/19 - - 8/205 9/62 5.30 (1.82-15.43) 0.002 Undetermined 29/241 1/27 0.30 (0.04-2.33) 0.250 29/253 1/19 0.61 (0.08-4.84) 0.639 23/205 8/62 0.77 (0.35-1.69) 0.509 CI, confidence interval; AOR, adjusted odds ratio. 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