Germline variation in the insulin-like growth factor pathway and risk of Barrett’s esophagus and esophageal adenocarcinoma

Abstract 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. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling, and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. 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 assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17,159 controls). 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=0.0090, 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. 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.

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173 Reduced Epidermal Growth Factor (EGF) Expression Is Associated with An Increased Risk for the Reflux-Induced Cascade Causing Barrett's Esophagus and Esophageal Adenocarcinoma

Gastroenterology ◽

10.1016/s0016-5085(08)60143-2 ◽

2008 ◽

Vol 134 (4) ◽

pp. A-29

Author(s):

Vivianda Menke ◽

Peter D. Siersema ◽

Leon M. Moons ◽

Katinka P. van Zoest ◽

Raymond G. Pot ◽

...

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Barrett’S Esophagus ◽

Esophageal Adenocarcinoma ◽

Barrett's Esophagus ◽

Increased Risk ◽

Epidermal Growth

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Development of Esophageal Adenocarcinoma in Patients with Barrett's Esophagus and High Grade Dysplasia Undergoing Survilence: A Meta-Analysis and Systematic Review

Gastrointestinal Endoscopy ◽

10.1016/j.gie.2006.03.030 ◽

2006 ◽

Vol 63 (5) ◽

pp. AB82 ◽

Cited By ~ 4

Author(s):

Srinivas R. Puli ◽

Amit Rastogi ◽

Sharad Mathur ◽

Ajay Bansal ◽

Prateek Sharma

Keyword(s):

Systematic Review ◽

Barrett’S Esophagus ◽

Esophageal Adenocarcinoma ◽

Barrett's Esophagus ◽

Meta Analysis ◽

High Grade Dysplasia ◽

High Grade

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Acid-suppressive medications and risk of esophageal adenocarcinoma in patients with Barrett’s esophagus: A systematic review and meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.11 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 11-11

Author(s):

Preet Paul Singh ◽

Siddharth Singh ◽

Sushil Kumar Garg ◽

Prasad G. Iyer ◽

Hashem El-Serag

Keyword(s):

Systematic Review ◽

Cohort Studies ◽

Barrett’S Esophagus ◽

Esophageal Adenocarcinoma ◽

Barrett's Esophagus ◽

Observational Studies ◽

Meta Analysis ◽

Number Needed To Treat ◽

Case Control Studies ◽

Inconsistency Index

11 Background: Acid-suppressive medications, particularly proton pump inhibitors (PPI), may modify risk of esophageal adenocarcinoma (EAC) in patients with Barrett’s esophagus (BE). We performed a systematic review and meta-analysis of studies evaluating the association between PPIs and histamine receptor antagonists (H2RA) and risk of EAC or high-grade dysplasia (BE-HGD) in patients with BE. Methods: Through a systematic search up to June 2013, we identified 7 observational studies (5 cohort studies and 2 case-control studies; 2,813 patients with BE, 317 cases of EAC and/or BE-HGD, 84.4% PPI users) reporting the association between PPIs or H2RA and EAC in patients with BE. Summary odds ratio (OR) with 95% confidence intervals (CI) was estimated using random effects model, and heterogeneity was measured using the inconsistency index (I2). Results: On meta-analysis, PPI use was associated with 71% reduction in EAC risk in patients with BE (adjusted OR, 0.29; 95% CI, 0.12-0.71). There was a trend toward a dose-response relationship with PPI use for >2 years protective against EAC [3 studies; PPI use >2 years vs. <2 years (as compared to no use): OR, 0.45 (0.19-1.06) vs. 1.09 (0.47-2.56)]. Considerable heterogeneity was observed in the overall analysis (I2=81%). On restricting analysis to 5 cohort studies, use of PPIs was consistently associated with a lower risk of EAC and/or BE-HGD (adjusted OR, 0.33; 95% CI, 0.19-0.58; I2=9%). H2RA use was not associated with decreased risk of EAC in patients with BE based on 2 studies (adjusted OR, 1.15; 95% CI, 0.77-1.72). Using a 67% summary risk reduction (derived from cohort studies) of EAC and/or BE-HGD with PPI use in patients with BE, and observed cumulative incidence rates of EAC and/or BE-HGD in patients with BE overall as 10.2 per 1,000 patient years, we estimate the number needed to treat with PPIs to prevent 1 case of EAC or BE-HGD in BE patients at 147. Conclusions: Based on meta-analysis of observational studies, the use of PPI, but not H2RA appears to be associated with a decreased risk of EAC and/or BE-HGD in patients with BE. PPI use should be considered in BE, and chemopreventive trials of PPIs in patients with BE are warranted.

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