Academic Journal
Multi-ancestry genome-wide association meta-analysis of hepatocellular carcinoma identifies 15 risk loci including MAP3K9, DHRS1, MTTP, and 8q24.21.
| Τίτλος: | Multi-ancestry genome-wide association meta-analysis of hepatocellular carcinoma identifies 15 risk loci including MAP3K9, DHRS1, MTTP, and 8q24.21. |
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| Συγγραφείς: | Chinaka I; Department of Medicine, St James' Hospital, Dublin, Ireland., Schofield A; Department of Immunology & Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, UK., Amos CI; Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA., Roberts LR; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA., Chen VL; Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA., Han Y; Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA., Hassan M; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Shetty S; National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK., Mann JP; Department of Immunology & Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, UK; National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK; Liver Unit (including small bowel transplantation), Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK. Electronic address: j.p.mann@bham.ac.uk. |
| Πηγή: | HGG advances [HGG Adv] 2026 Oct 08; Vol. 7 (4), pp. 100639. Date of Electronic Publication: 2026 Jun 25. |
| Τύπος έκδοσης: | Journal Article; Meta-Analysis |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Inc Country of Publication: United States NLM ID: 101772885 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2666-2477 (Electronic) Linking ISSN: 26662477 NLM ISO Abbreviation: HGG Adv Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: New York : Elsevier Inc., [2020]- |
| Ιατρικοί όροι (MeSH): | Carcinoma, Hepatocellular*/genetics , Carcinoma, Hepatocellular*/pathology , Liver Neoplasms*/genetics , Liver Neoplasms*/pathology , Chromosomes, Human, Pair 8*/genetics , MAP Kinase Kinase Kinases*/genetics , Genome-Wide Association Study* , Genetic Predisposition to Disease* , Genetic Loci*, Humans ; Polymorphism, Single Nucleotide |
| Περίληψη: | Hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally, often arising on a background of cirrhosis. Here, we aimed to establish genetic drivers of all-cause HCC across ancestries in a large meta-analysis. We included 15 cohorts comprising 17,697 HCC affected individuals and 2,715,683 control subjects in this meta-analysis. We found 15 genome-wide significant (p < 5 × 10-8) germline loci, including in/near GCKR, MTTP, ADH5, 8q24.21 (nearest gene MYC), MAP3K9, and GABPB2, and a further two loci found on transcriptome- and regulome-wide association analyses. MAP3K9, TERT, and GABPB2 variants act independently of cirrhosis on both colocalization analysis and sensitivity analyses. There was significant ancestral heterogeneity in six loci including variants in the HLA locus that had divergent effects on HCC risk between East Asian and European ancestries. Fine mapping identified 11 potentially causal coding variants, including p.Leu446Pro (c.1337T>C) in GCKR and p.Asp423Glu (c.1269C>T) in MEN1. MEN1, 8q24.21 (nearest gene MYC), and TERT are all involved in the β-catenin pathway transactivation complex. Transcriptome-wide analysis identified enrichment of germline-encoded DHRS1 in HCC. Regulome-wide analysis replicated the germline signal for EPHA2 and found a chromatin-accessible region containing genes ZNF367 and HABP4. Finally, we demonstrated that population-level genetic architecture for HCC overlaps with steatotic and viral liver disease, and individuals with genetic risk for lower body mass index have higher risk of HCC. Genetic risk for HCC is determined by germline susceptibility to β-catenin pathway activation and cirrhosis. HCC is driven by both heterogeneous and homogeneous genetic factors across ancestries. (Copyright © 2026 The Author(s). Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of interests V.L.C. received grants from AstraZeneca, Takeda, Ipsen, and KOWA, paid to the University of Michigan. S.S. has received honorarium from Astra Zeneca. |
| Contributed Indexing: | Keywords: cirrhosis; genomics; liver cancer; steatosis |
| Substance Nomenclature: | EC 2.7.11.25 (MAP Kinase Kinase Kinases) |
| Entry Date(s): | Date Created: 20260626 Date Completed: 20261008 Latest Revision: 20261016 |
| Update Code: | 20261017 |
| PubMed Central ID: | PMC13445208 |
| DOI: | 10.1016/j.xhgg.2026.100639 |
| PMID: | 42357869 |
| Βάση Δεδομένων: | MEDLINE |
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