Abstract 1588: Germline variation in DNA repair genes and risk of Barrett's esophagus and esophageal adenocarcinoma

Abstract

Abstract Incidence of esophageal adenocarcinoma (EA) has risen substantially in Western countries over recent decades. Established risk factors for EA and its precursor lesion, Barrett’s esophagus (BE), include reflux, obesity, and tobacco smoking. Inherited genetic variation also influences disease risk, although only a limited number of susceptibility loci have been identified. Genomic analyses of EA tumors have revealed a distinctive mutational signature, high mutational burden, and extensive somatic chromosome alterations, features also observed in high-risk BE tissue. To explore whether germline variation in DNA repair-related genes may be associated with altered disease susceptibility, we analyzed data from a recent meta-analysis of genome-wide association studies (GWAS) encompassing 4,112 EA cases, 6,167 BE cases, and 17,159 controls, representing the largest sample size assembled for these conditions. Using a gene-based testing approach (VEGAS2), we assessed 263 DNA repair-related genes and found that variation in NEIL2, a mediator of base excision repair (BER), was significantly associated with risk of BE (P=1.4×10-5, q<0.05). No other gene-level associations with BE or EA survived correction for multiple comparisons. SNP-level analysis of 239 polymorphisms at the NEIL2 locus revealed six variants strongly associated with altered risk of BE (P<5×10-5, q<0.01), with the index SNP classified as an intronic eQTL for NEIL2 in esophageal tissue. Four of these SNPs were also associated with risk of EA (P<0.05), with odds ratios in the same direction and of similar magnitude. Our results provide evidence that germline genetic variation in a DNA glycosylase enzyme (NEIL2) may influence risk of BE/EA, and suggest a potential novel biological role for altered BER in BE/EA pathogenesis. Citation Format: Matthew F. Buas, Li Yan, Xuan Peng, Qianya Qi, Jianhong Chen, Aaron Thrift, Qianchuan He, Lynn Onstad, Puya Gharahkhani, Stuart MacGregor, Thomas L. Vaughan, Margaret M. Madeleine. Germline variation in DNA repair genes and risk of Barrett's esophagus and esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1588.