ASPO Abstracts
Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma
Category: Molecular Epidemiology & Environment
Conference Year: 2021
Abstract Body:
Purpose: Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor,
Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains
unexplained. Strong epidemiologic associations between central obesity and risk of BE/EAC have suggested a
role for metabolic signaling disturbances, such as in the insulin-like growth factor (IGF) axis, in the
pathophysiology of BE/EAC. Targeted assessment of genetic variation in such biologically relevant pathways, may
identify missed susceptibility signals. Hence, we sought to examine the association between germline variation in
the IGF pathway and its component genes with risk of BE and EAC.
Methods: Principal components analysis (PCA) was employed to evaluate pathway-level and gene-level
associations with BE/EAC, using genotypes for 270 SNPs in or near 12 IGF-related genes, ascertained from 3295
BE cases, 2515 EAC cases, and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium
(BEACON) GWAS. Gene-level signals were also assessed using Multi-marker Analysis of GenoMic Annotation
(MAGMA) and SNP summary statistics from BEACON, and an extended BE/EAC GWAS meta-analysis (6167 BE
cases, 4112 EAC cases, and 17,159 controls).
Results: Global variation in the IGF pathway was associated with risk of BE (P=0.0015). Gene-level associations
with BE were observed for GHR (growth hormone receptor; p=0.00046, FDR q=0.0056) and IGF1R (IGF1
receptor; p=0.00903, q=0.0542). These gene-level signals remained significant at q<0.1 when assessed using
data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC.
Conclusions: This study represents the most comprehensive evaluation to date of inherited genetic variation in the
IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface
receptors, GHR and IGF1R, may influence risk of BE.
Keywords: IGF pathway, germline variants, Barrett's esophagus, esophageal adenocarcinoma