Cumulative Evidence for Associations between Genetic Variants and Risk of Esophageal Cancer

Background: A large number of studies have been conducted to investigate associations between genetic variants and esophageal cancer risk in the past several decades. However, findings from these studies have been generally inconsistent. We aimed to provide a summary of the current understanding of the genetic architecture of esophageal cancer susceptibility.

Methods: We performed a comprehensive field synopsis and meta-analysis to evaluate associations between 95 variants in 70 genes or loci and esophageal cancer risk using data from 304 eligible publications, including 104,904 cases and 159,797 controls, through screening a total of 21,328 citations. We graded levels of cumulative epidemiologic evidence of a significant association with esophageal cancer using the Venice criteria and false-positive report probability tests. We constructed functional annotations for these variants using data from the Encyclopedia of DNA Elements Project and other databases.

Results: Thirty variants were nominally significantly associated with esophageal cancer risk. Cumulative epidemiologic evidence of a significant association with overall esophageal cancer, esophageal squamous cell carcinoma, or esophageal adenocarcinoma was strong for 13 variants in or near 13 genes (ADH1B, BARX1, CDKN1A, CHEK2, CLPTM1L, CRTC1, CYP1A1, EGF, LTA, MIR34BC, PLCE1, PTEN, and PTGS2). Bioinformatics analysis suggested that these variants and others correlated with them might fall in putative functional regions.

Conclusions: Our study summarizes the current literature on the genetic architecture of esophageal cancer susceptibility and identifies several potential polymorphisms that could be involved in esophageal cancer susceptibility.

Impact: These findings provide direction for future studies to identify new genetic factors for esophageal cancer.