Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett's esophagus and esophageal adenocarcinoma Journal Article
| Authors: | Yan, L.; He, Q.; Verma, S. P.; Zhang, X.; Giel, A. S.; Maj, C.; Graz, K.; Naderi, E.; Chen, J.; Ali, M. W.; Gharahkhani, P.; Shu, X.; Offit, K.; Shah, P. M.; Gerdes, H.; Molena, D.; Srivastava, A.; MacGregor, S.; BEACON Consortium; OCCAMS Consortium; Esophageal Cancer Consortium; Palles, C.; Thieme, R.; Vieth, M.; Gockel, I.; Vaughan, T. L.; Schumacher, J.; Buas, M. F. |
| Article Title: | Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett's esophagus and esophageal adenocarcinoma |
| 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. © 2025 The Authors |
| Keywords: | controlled study; unclassified drug; human cell; major clinical study; single nucleotide polymorphism; microrna; mitogen activated protein kinase kinase 2; protein; genome-wide association study; gene mapping; gene interaction; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; plasmid; methylated dna protein cysteine methyltransferase; esophageal adenocarcinoma; protein kinase; protein kinase c alpha; dna isolation; transcription factor gata 4; genotyping; protein kinase c epsilon; cyclin dependent kinase inhibitor 2b; barrett esophagus; phosphodiesterase; nuclear factor; barrett's esophagus; machine learning; gene-gene interaction; human; male; female; article; luciferase assay; phosphodiesterase 2a; colecalciferol 24 hydroxylase; axis inhibition protein 1; knowledge-guided filtering; large scale computing; post-gwas; b lymphocyte kinase; cytochrome p450 4a11; disks large homolog 2; terf1 interacting nuclear factor; thioredoxin related transmembrane protein 2; g g interaction; oe19 cell line; oe33 cell line |
| Journal Title: | Human Genetics and Genomics Advances |
| Volume: | 6 |
| Issue: | 2 |
| ISSN: | 2666-2477 |
| Publisher: | Cell Press |
| Date Published: | 2025-04-10 |
| Start Page: | 100399 |
| Language: | English |
| DOI: | 10.1016/j.xhgg.2025.100399 |
| PUBMED: | 39755942 |
| PROVIDER: | scopus |
| PMCID: | PMC11815673 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Matthew F. Buas -- Source: Scopus |
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