Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett's esophagus and esophageal adenocarcinoma

Yan L, He Q, Verma SP, Zhang X, Giel AS, Maj C, Graz K, Naderi E, Chen J, Ali MW, Gharahkhani P, Shu X, Offit K, Shah PM, Gerdes H, Molena D, Srivastava A, MacGregor S, Palles C, Thieme R, Vieth M, Gockel I, Vaughan TL, Schumacher J, Buas MF (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Human Genetics and Genomics Advances Cell Press

Book Volume: 6

Article Number: 100399

Journal Issue: 2

DOI: 10.1016/j.xhgg.2025.100399

Abstract

Inherited genetics represents an important contributor to risk of esophageal adenocarcinoma (EAC), and its precursor Barrett's esophagus (BE). Genome-wide association studies have identified ∼30 susceptibility variants for BE/EAC, yet genetic interactions remain unexamined. To address challenges in large-scale G×G scans, we combined knowledge-guided filtering and machine learning approaches, focusing on genes with (1) known/plausible links to BE/EAC pathogenesis (n = 493) or (2) prior evidence of biological interactions (n = 4,196). Approximately 75 × 106 SNP×SNP interactions were screened via hierarchical group lasso (glinternet) using BEACON GWAS data. The top ∼2,000 interactions retained in each scan were prioritized using p values from single logistic models. Identical scans were repeated among males only (78%), with two independent GWAS datasets used for replication. In overall and male-specific primary replications, 11 of 187 and 20 of 191 interactions satisfied p < 0.05, respectively. The strongest evidence for secondary replication was for rs17744726×rs3217992 among males, with consistent directionality across all cohorts (Pmeta = 2.19 × 10−8); rs3217992 “T” was associated with reduced risk only in individuals homozygous for rs17744726 “G.” Rs3217992 maps to the CDKN2B 3′ UTR and reportedly disrupts microRNA-mediated repression. Rs17744726 maps to an intronic enhancer region in BLK. Through in silico prioritization and experimental validation, we identified a nearby proxy variant (rs4841556) as a functional modulator of enhancer activity. Enhancer-gene mapping and eQTLs implicated BLK and FAM167A as targets. The first systematic G×G investigation in BE/EAC, this study uncovers differential risk associations for CDKN2B variation by BLK genotype, suggesting novel biological dependency between two risk loci encoding key mediators of tumor suppression and inflammation.

Involved external institutions

Roswell Park Cancer Institute US United States (USA) (US) Fred Hutchinson Cancer Research Center US United States (USA) (US) Memorial Sloan Kettering Cancer Center US United States (USA) (US) Universitätsklinikum Gießen und Marburg (UKGM) DE Germany (DE) University of Virginia (UVA) US United States (USA) (US) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) AU Australia (AU) University of Birmingham GB United Kingdom (GB) Universitätsklinikum Leipzig DE Germany (DE) Klinikum Bayreuth DE Germany (DE)

How to cite

APA:

Yan, L., He, Q., Verma, S.P., Zhang, X., Giel, A.S., Maj, C.,... Buas, M.F. (2025). Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett's esophagus and esophageal adenocarcinoma. Human Genetics and Genomics Advances, 6(2). https://doi.org/10.1016/j.xhgg.2025.100399

MLA:

Yan, Li, et al. "Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett's esophagus and esophageal adenocarcinoma." Human Genetics and Genomics Advances 6.2 (2025).

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