Background & Aims Hepatocellular carcinoma (HCC) is the third top cause of cancer death globally, often arising on a background of cirrhosis. Here, we aimed to establish novel genetic drivers of HCC across ancestries at a population level through a large meta-analysis of all-cause HCC. Approach & Results We included 15 cohorts comprising 17,329 HCC cases and 2,424,298 controls in this meta-analysis. We found 15 genome-wide significant (P < 5x10-8) germline loci, 6 novel in/near GCKR, MTTP, ADH5, MYC, MAP3K9, and GABPB2. MAP3K9, TERT, and GABPB2 variants act independently of cirrhosis on both co-localisation analysis and sensitivity analyses. There was significant ancestral heterogeneity in 6 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 in GCKR and p.Asp418Glu in MEN1. MEN1, MYC, and TERT are all involved in the beta-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 novel 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 BMI have higher risk of HCC. Conclusions Genetic risk for HCC is determined by germline susceptibility to beta-catenin pathway activation and cirrhosis. HCC is driven by both heterogenous and homogenous genetic factors across ancestries, which require further ancestral diversity in liver GWAS to fully dissect.
Chinaka et al. (Wed,) studied this question.