Abstract 2571: Genetic variations in telomere maintenance pathway genes are associated with risk of esophageal cancer.

Abstract

Abstract Many studies have shown the association of telomere dysfunction with aging and cancer development. We hypothesize that genetic variations in telomere maintenance genes may modulate esophageal cancer risk. To test this hypothesis, we comprehensively assessed the association of 616 SNPs in 45 telomere maintenance pathway genes in 602 esophageal adenocarcinoma cases and 1,512 healthy controls. Unconditional multivariate logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) while adjusting for age, gender, and smoking status. In single SNP analysis, a total of 77 SNPs had P value < 0.05. 5 SNPs remained significant after adjusting for multiple comparisons at FDR < 0.10 including 3 SNPs in PINX1 gene and 2 SNPs in TPP1 gene. The most significant association was observed for rs9657541 in PINX1 gene that exhibited a significantly reduced risk of esophageal cancer in dominant model (OR = 0.62, 95% CI = 0.50-0.77, P = 1.54×10−5, FDR = 0.020). Cumulative effects of SNPs were assessed by the number of unfavorable genotypes. Each subject was classified into low (zero unfavorable genotype), medium (one to three unfavorable genotypes), and high-risk groups (more than three unfavorable genotypes). Compared with the low-risk group, the OR was 1.58 (95% CI = 1.20-2.09) for the median-risk group and 2.57 (95% CI = 1.87-3.54) for the high-risk group. Classification and regression tree (CART) analysis was performed to identify genetic profiles that can classify individuals into differential risk of esophageal cancer. CART analysis identified 3 terminal nodes. Compared to terminal node 1, individuals in terminal nodes 2 and 3 had significantly increased risks of esophageal cancer with ORs of 1.43 (95% CI = 1.13-1.80) and 2.46 (95% CI = 1.81-3.34), respectively. We also performed gene-based analysis to determine the combined effect of SNPs within a gene region and identified four genes (TPP1, PINX1, TNKS, TERF1) significantly associated with the risk of esophageal cancer. In conclusion, our results suggest that genetic variants in telomere maintenance pathway genes may contribute to the altered risk of esophageal cancer, both individually and jointly. Citation Format: Yuanqing Ye, Jaffer Ajani, Xifeng Wu. Genetic variations in telomere maintenance pathway genes are associated with risk of esophageal 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 2571. doi:10.1158/1538-7445.AM2013-2571