Abstract
Incidence of esophageal adenocarcinoma (EA) has increased substantially in recent decades. Multiple risk factors have been identified for EA and its precursor, Barrett’s esophagus (BE), such as reflux, European ancestry, male sex, obesity, and tobacco smoking, and several germline genetic variants were recently associated with disease risk. Using data from the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls, we examined single nucleotide polymorphisms (SNPs) that potentially affect the biogenesis or biological activity of microRNAs (miRNAs), small non-coding RNAs implicated in post-transcriptional gene regulation, and deregulated in many cancers, including EA. Polymorphisms in three classes of genes were examined for association with risk of EA or BE: miRNA biogenesis genes (157 SNPs, 21 genes); miRNA gene loci (234 SNPs, 210 genes); and miRNA-targeted mRNAs (177 SNPs, 158 genes). Nominal associations (P<0.05) of 29 SNPs with EA risk, and 25 SNPs with BE risk, were observed. None remained significant after correction for multiple comparisons (FDR q>0.50), and we did not find evidence for interactions between variants analyzed and two risk factors for EA/BE (smoking and obesity). This analysis provides the most extensive assessment to date of miRNA-related SNPs in relation to risk of EA and BE. While common genetic variants within components of the miRNA biogenesis core pathway appear unlikely to modulate susceptibility to EA or BE, further studies may be warranted to examine potential associations between unassessed variants in miRNA genes and targets with disease risk.
Highlights
Incidence of esophageal adenocarcinoma (EA) in Western countries has risen sharply in recent decades, while median survival remains less than one year [1]
The Barrett’s and Esophageal Adenocarcinoma Genetic Susceptibility Study (BEAGESS) included men and women diagnosed with EA or Barrett’s esophagus (BE), and control participants pooled from 14 individual studies conducted in Western Europe, Australia, and North America over the past twenty years
All EA and BE case participants were confirmed by histologic examination, and a set of population control individuals was drawn from the included Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) studies to serve as a comparison group for both EA and BE case participants
Summary
Incidence of esophageal adenocarcinoma (EA) in Western countries has risen sharply in recent decades, while median survival remains less than one year [1]. Candidate-gene-based studies have associated altered risk of EA or BE with DNA polymorphisms in genes that function in a wide range of biological pathways (inflammation, detoxification, DNA repair, angiogenesis, and apoptosis) [3,4,5,6,7,8,9,10,11,12,13], while a recent linkage-based genetic analysis of sibling pairs provided preliminary evidence for several novel germline mutations [14] These studies have been limited by small sample sizes and the need for validation. In the last few years, large genome-wide association studies of BE and EA identified multiple SNPs significantly associated with disease risk [15,16,17,18], including variants located in three transcription factors, a transcriptional co-activator, and the major histocompatibility complex locus, none of which were previously implicated by candidate-based studies
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