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

Dighe SG, Chen J, Yan L, He Q, Gharahkhani P, Onstad L, Levine DM, Palles C, Ye W, Gammon MD, Iyer PG, Anderson LA, Liu G, Wu AH, Dai JY, Chow WH, Risch HA, Lagergren J, Shaheen NJ, Bernstein L, Corley DA, Prenen H, De Caestecker J, MacDonald D, Moayyedi P, Barr H, Love SB, Chegwidden L, Attwood S, Watson P, Harrison R, Ott K, Moebus S, Venerito M, Lang H, Mayershofer R, Knapp M, Veits L, Gerges C, Weismüller J, Gockel I, Vashist Y, Nöthen MM, Izbicki JR, Manner H, Neuhaus H, Rösch T, Böhmer AC, Hölscher AH, Anders M, Pech O, Schumacher B, Schmidt C, Schmidt T, Noder T, Lorenz D, Vieth M, May A, Hess T, Kreuser N, Becker J, Ell C, Ambrosone CB, Moysich KB, MacGregor S, Tomlinson I, Whiteman DC, Jankowski J, Schumacher J, Vaughan TL, Madeleine MM, Hardie LJ, Buas MF (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 42

Pages Range: 369-377

Journal Issue: 3

DOI: 10.1093/carcin/bgaa132

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 component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (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, false discovery rate 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.

Involved external institutions

University of Washington United States (USA) (US) University of Birmingham United Kingdom (GB) Karolinska Institute Sweden (SE) University of North Carolina at Chapel Hill United States (USA) (US) Mayo Clinic United States (USA) (US) Queen's University United Kingdom (GB) Princess Margaret Cancer Centre / Princess Margaret Hospital Canada (CA) Keck School of Medicine of USC United States (USA) (US) Fred Hutchinson Cancer Research Center United States (USA) (US) University of Texas MD Anderson Cancer Center United States (USA) (US) Yale University United States (USA) (US) City of Hope Medical Center United States (USA) (US) Kaiser Permanente United States (USA) (US) Hospital Network Antwerp / Ziekenhuis Netwerk Antwerpen (ZNA) Belgium (BE) University Hospitals of Leicester NHS Trust United Kingdom (GB) University of British Columbia Canada (CA) McMaster University Canada (CA) Gloucestershire Hospitals United Kingdom (GB) University of Oxford United Kingdom (GB) Sana Kliniken AG Germany (DE) Roswell Park Cancer Institute United States (USA) (US) King's Mill Hospital United Kingdom (GB) University of Cambridge United Kingdom (GB) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Leicester Royal Infirmary United Kingdom (GB) Ruprecht-Karls-Universität Heidelberg Germany (DE) Universitätsklinikum Essen Germany (DE) Otto-von-Guericke-Universität Magdeburg Germany (DE) Universitätsmedizin der Johannes Gutenberg-Universität Mainz Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Klinikum Bayreuth Germany (DE) Evangelisches Krankenhaus Düsseldorf Germany (DE) Universitätsklinikum Leipzig Germany (DE) Asklepios Kliniken Germany (DE) North Tyneside General Hospital United Kingdom (GB) Royal Victoria Hospital United Kingdom (GB) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Sanofi-Aventis Groupe France (FR) Elisabeth-Krankenhaus Essen Germany (DE) Krankenhaus Barmherzige Brüder Germany (DE) Universität zu Köln Germany (DE) Asklepios Klinik Wiesbaden Germany (DE) Universitätsklinikum Gießen und Marburg (UKGM) Germany (DE) University of Leeds United Kingdom (GB)

How to cite

APA:

Dighe, S.G., Chen, J., Yan, L., He, Q., Gharahkhani, P., Onstad, L.,... Buas, M.F. (2021). Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma. Carcinogenesis, 42(3), 369-377. https://doi.org/10.1093/carcin/bgaa132

MLA:

Dighe, Shruti G., et al. "Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma." Carcinogenesis 42.3 (2021): 369-377.

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