Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma

Abstract

Esophageal adenocarcinoma (EA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation, operating downstream of disease-associated exposures, is considered an important contributor to EA pathogenesis. Several risk factors have been identified for EA and its precursor, Barrett’s esophagus (BE), including symptomatic reflux, obesity, and smoking. The role of inherited genetic susceptibility remains an area of active investigation. To explore whether germline variation related to inflammatory processes influences susceptibility to BE/EA, we used data from a genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls. Our analysis included 7,863 single nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signaling, oxidative stress, human leukocyte antigen, and NFκB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. We identified a significant signal for the COX pathway in relation to BE risk (P=0.0059, FDR q=0.03), and in gene-level analyses found an association with MGST1 (microsomal glutathione-S-transferase 1; P=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Of these, four were subsequently confirmed (P<5.5 × 10−5) in a meta-analysis encompassing an independent set of 1,851 BE cases and 3,496 controls. Three of these SNPs (rs3852575, rs73112090, rs4149204) were associated with similar elevations in EA risk. This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/EA, and suggests that variants in MGST1 influence disease susceptibility.

The Evolving Genomic Landscape of Barrett’s Esophagus and Esophageal Adenocarcinoma

“…Variants in the cyclooxygenase (COX) pathway were significantly associated with risk of BE. Gene-level analyses identified an association with MGST1 (on chromosome 12p12), and a meta-analysis, which added BE and control participants from the Wellcome Trust GWAS, confirmed associations between 4 SNPs and risk of BE (Figure 2, Supplementary Table 2) 60 . Analyses of GWAS data examining the role of germline variation in other pathways, including the biogenesis and activity of microRNAs 61 , androgens 62 , and the estrogen and oxytocin pathways 63 , also indicated associations, but these have not been replicated.…”

Metaplasia: tissue injury adaptation and a precursor to the dysplasia–cancer sequence

“…In the case of Barrett oesophagus, tissue is accessible via upper endoscopy. To that end, whole and paired exomic sequencing of normal and Barrett oesophagus has unravelled a crucial role for mutations of TP53 and CDKN2A 124–126 . Although the exact consequences of TP53 mutations in the development of Barrett oesophagus remain to be elucidated, it is possible that such mutations might serve as a gatekeeper for the maintenance of metaplasia and/or drive the conversion of metaplasia to low-grade dysplasia in the oesophagus 124 and perhaps the stomach as well 127 .…”

Oesophageal cancer

“…19 Research has now identified risk loci for Barrett's oesophagus associated carcinogenesis. [20][21][22][23] These findings could be used for research examining tailored prevention in individuals at high risk of OAC. There is presently limited scientific evidence supporting specific preventive measures in OAC, 24 but aspirin and antireflux therapy are being tested an RCT of patients with Barrett's oesophagus (AspECT).…”