Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett’s esophagus and esophageal adenocarcinoma
Summary: 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 chall...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-04-01
|
| Series: | HGG Advances |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247725000028 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832582072928043008 |
|---|---|
| author | Li Yan Qianchuan He Shiv P. Verma Xu Zhang Ann-Sophie Giel Carlo Maj Kathryn Graz Elnaz Naderi Jianhong Chen Mourad Wagdy Ali Puya Gharahkhani Xiang Shu Kenneth Offit Pari M. Shah Hans Gerdes Daniela Molena Amitabh Srivastava Stuart MacGregor Claire Palles René Thieme Michael Vieth Ines Gockel Thomas L. Vaughan Johannes Schumacher Matthew F. Buas |
| author_facet | Li Yan Qianchuan He Shiv P. Verma Xu Zhang Ann-Sophie Giel Carlo Maj Kathryn Graz Elnaz Naderi Jianhong Chen Mourad Wagdy Ali Puya Gharahkhani Xiang Shu Kenneth Offit Pari M. Shah Hans Gerdes Daniela Molena Amitabh Srivastava Stuart MacGregor Claire Palles René Thieme Michael Vieth Ines Gockel Thomas L. Vaughan Johannes Schumacher Matthew F. Buas |
| author_sort | Li Yan |
| collection | DOAJ |
| description | Summary: 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. |
| format | Article |
| id | doaj-art-06e1f892d08e46b4ad7ab6fabb2ed584 |
| institution | Kabale University |
| issn | 2666-2477 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | HGG Advances |
| spelling | doaj-art-06e1f892d08e46b4ad7ab6fabb2ed5842025-01-30T05:15:00ZengElsevierHGG Advances2666-24772025-04-0162100399Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett’s esophagus and esophageal adenocarcinomaLi Yan0Qianchuan He1Shiv P. Verma2Xu Zhang3Ann-Sophie Giel4Carlo Maj5Kathryn Graz6Elnaz Naderi7Jianhong Chen8Mourad Wagdy Ali9Puya Gharahkhani10Xiang Shu11Kenneth Offit12Pari M. Shah13Hans Gerdes14Daniela Molena15Amitabh Srivastava16Stuart MacGregor17Claire Palles18René Thieme19Michael Vieth20Ines Gockel21Thomas L. Vaughan22Johannes Schumacher23Matthew F. Buas24Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USAPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USADepartment of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USADepartment of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USACenter for Human Genetics, University Hospital of Marburg, Marburg, GermanyCenter for Human Genetics, University Hospital of Marburg, Marburg, GermanyDepartment of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USADepartment of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USADepartment of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USADepartment of Genome Sciences, School of Medicine, University of Virginia, Charlottesville, VA, USAQIMR Berghofer Medical Research Institute, Brisbane, QLD, AustraliaDepartment of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USAClinical Genetics, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USAGastroenterology and Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USAGastroenterology and Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USAThoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USADepartment of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USAQIMR Berghofer Medical Research Institute, Brisbane, QLD, AustraliaDepartment of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UKDepartment of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, GermanyInstitute of Pathology, Friedrich-Alexander-Universiät Erlangen-Nürnberg, Klinikum Bayreuth, Bayreuth, GermanyDepartment of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, GermanyPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, School of Public Health, Seattle, WA, USACenter for Human Genetics, University Hospital of Marburg, Marburg, GermanyDepartment of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2666247725000028gene-gene interactionpost-GWASknowledge-guided filteringmachine learninglarge scale computingBarrett’s esophagus |
| spellingShingle | Li Yan Qianchuan He Shiv P. Verma Xu Zhang Ann-Sophie Giel Carlo Maj Kathryn Graz Elnaz Naderi Jianhong Chen Mourad Wagdy Ali Puya Gharahkhani Xiang Shu Kenneth Offit Pari M. Shah Hans Gerdes Daniela Molena Amitabh Srivastava Stuart MacGregor Claire Palles René Thieme Michael Vieth Ines Gockel Thomas L. Vaughan Johannes Schumacher Matthew F. Buas Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett’s esophagus and esophageal adenocarcinoma HGG Advances gene-gene interaction post-GWAS knowledge-guided filtering machine learning large scale computing Barrett’s esophagus |
| title | Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett’s esophagus and esophageal adenocarcinoma |
| title_full | Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett’s esophagus and esophageal adenocarcinoma |
| title_fullStr | Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett’s esophagus and esophageal adenocarcinoma |
| title_full_unstemmed | Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett’s esophagus and esophageal adenocarcinoma |
| title_short | Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett’s esophagus and esophageal adenocarcinoma |
| title_sort | biologically targeted discovery replication scan identifies g g interaction in relation to risk of barrett s esophagus and esophageal adenocarcinoma |
| topic | gene-gene interaction post-GWAS knowledge-guided filtering machine learning large scale computing Barrett’s esophagus |
| url | http://www.sciencedirect.com/science/article/pii/S2666247725000028 |
| work_keys_str_mv | AT liyan biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT qianchuanhe biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT shivpverma biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT xuzhang biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT annsophiegiel biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT carlomaj biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT kathryngraz biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT elnaznaderi biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT jianhongchen biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT mouradwagdyali biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT puyagharahkhani biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT xiangshu biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT kennethoffit biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT parimshah biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT hansgerdes biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT danielamolena biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT amitabhsrivastava biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT stuartmacgregor biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT clairepalles biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT renethieme biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT michaelvieth biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT inesgockel biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT thomaslvaughan biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT johannesschumacher biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma AT matthewfbuas biologicallytargeteddiscoveryreplicationscanidentifiesgginteractioninrelationtoriskofbarrettsesophagusandesophagealadenocarcinoma |