Abstract
Abstract The Notch signaling pathway drives proliferation, differentiation, apoptosis, cell fate choices, and has a key role in the regulation of stem cells in a variety of cancers. In this study, we applied a pathway-based approach to evaluate the associations between single nucleotide polymorphisms in Notch signaling pathway and ovarian cancer risk, survival, and response to chemotherapy. Towards this, we systematically genotyped 139 SNPs from 10 genes in the pathway in 339 Caucasian ovarian cancer cases and 349 Caucasian healthy controls. Individually, four SNPs were significantly associated with the ovarian cancer risk. The most significant SNP was NOTCH4: rs397081, with an adjusted odds ratio (OR) of 0.38 (95% CI = 0.22-0.66, P=0.00057). A highly significant gene-dosage effect was observed for these top variants (P for trend < 0.00001) with those carrying ≥ 3 risk genotypes having a nearly 6-fold increase in risk (OR = 5.67, 95% CI = 2.58 - 12.44] . Classification and regression tree (CART) analysis further revealed potential higher order gene-gene interactions between these four SNPs, with the highest risk group having almost 7-fold increased risk. Ten SNPs were significantly associated with overall survival, of which the strongest association was identified for NOTCH4: rs3131290 (OR = 0.48, 95% CI = 0.27-0.84). Cumulative effect analysis showed that multiple adverse genotypes had a significant dose-dependent effect on overall survival. The median survival times for individuals carrying ≤3, 4 to 6, and ≥7 of these adverse genotypes were >186.3, 62.82, and 28.58 months, respectively. Similarly, a significant association was identified between a poor response to platinum-based chemotherapy and the number of unfavorable SNPs (P for trend < 0.0001). Our findings suggest that genetic variants in the Notch signaling pathway are associated with ovarian cancer risk and could serve as potential predictors of clinical outcomes in ovarian cancer patients. Citation Format: Enping Xu, Karen H. Lu, Michelle AT Hildebrandt, Maosheng Huang, Xifeng Wu, Dong Liang. Genetic variants in Notch signaling pathway and ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4843. doi:10.1158/1538-7445.AM2013-4843
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