Abstract
Abstract Nucleotide excision repair (NER) pathway is critical for protecting against damage from carcinogens. In this case-control study, we evaluated the associations between genetic variations in NER pathway and ovarian cancer risk in 339 Caucasian ovarian cancer cases and 349 Caucasian healthy controls. A comprehensive panel of 217 SNPs in 28 NER pathway genes was analyzed to assess their association with ovarian cancer risk. For the cases who received surgery and platinum-based chemotherapy, we also analyzed the association of these SNPs with overall survival and response to chemotherapy. Individually, 12 SNPs were significantly associated with the ovarian cancer risk. The most significant association was observed for SNP rs4150667 from GTF2H1 (OR = 0.64, 95% CI 0.47- 0.86). A strong gene-dosage effect was observed when these top 12 SNPs were combined for unfavorable genotype analysis. Compared to subjects carrying ≤ 2 unfavorable genotypes, individuals carrying 3 (OR = 2.11, 95% CI = 1.32−3.39), 4 (OR = 2.32, 95% CI = 1.47 − 3.66) or ≥ 5 (OR = 4.31, 95% CI = 2.75 − 6.78) unfavorable genotypes exhibited significantly increased risk for ovarian cancer (P for trend < 0.0001). Classification and regression tree (CART) analysis further revealed potential high order gene-gene interaction among the top 12 SNPs and identified 7 terminal nodes with the percentage of ovarian cancer cases in each terminal node range from 27% to 64%. In the clinical outcome study, there were 10 SNPs that exhibited significant association with overall survival. The unfavorable genotype analysis showed the median survival times for individuals carrying ≤3, 4∼7, and ≥ 8 unfavorable genotypes were 83.3, 40.0, and 24.7 months, respectively, indicating a strong gene-dosage effect (P for trend < 0.0001). We also observed significant gene-dosage effect in chemotherapy response. In summary, this pathway-based approach demonstrated that increasing numbers of unfavorable genotypes in the NER predispose susceptible individuals to increased risk of ovarian cancer and affect clinical outcomes in ovarian cancer patients. These findings warrant further replications in independent populations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3593.
Published Version
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