Home›Gastroenterology› 15 germline loci associated with hepatocellular carcinoma identified across multiple ancestries
15 germline loci associated with hepatocellular carcinoma identified across multiple ancestriesGenetic Variants Linked to Risk of Liver Cancer Identified
HGG advancesPublished October 10, 2026Study authors: Chinaka Ifechukwuamaka, Schofield Annabelle, Amos Christopher I, Roberts Lewis R, Chen Vincent L, Ha…PubMed ↗DOI ↗Editorial oversight: Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease
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Key Takeaway
Note that 15 germline loci and 11 potentially causal coding variants are associated with hepatocellular carcinoma.
This meta-analysis evaluates genome-wide significant germline loci associated with hepatocellular carcinoma across a large sample of 17,697 affected individuals and 2,715,683 control subjects. The analysis identified 15 loci, including GCKR, MTTP, ADH5, 8q24.21, MAP3K9, and GABPB2, with p-values < 5 x 10^-8. Additionally, the study identified 11 potentially causal coding variants, such as p.Leu446Pro in GCKR and p.Asp423Glu in MEN1.
Further analysis revealed significant ancestral heterogeneity in six loci, including the HLA locus. Transcriptome-wide and regulome-wide analyses provided additional evidence, including the enrichment of germline-encoded DHRS1 and replicated signals for EPHA2. Notably, variants in MAP3K9, TERT, and GABPB2 were found to act independently of cirrhosis.
While the study identifies several potentially causal variants, these are not confirmed as causal. The findings provide a foundation for understanding genetic drivers of hepatocellular carcinoma across different ancestries. Clinical application is currently focused on identifying risk factors and genetic drivers rather than immediate therapeutic interventions.
How this fits prior evidence
This meta-analysis addresses a gap in the genetic understanding of hepatocellular carcinoma by identifying 15 germline loci and 11 potentially causal coding variants. While prior coverage focused on treatment modalities such as pembrolizumab, regorafenib, and cabozantinib for advanced hepatocellular carcinoma, or the efficacy of HAIC combined with TKI and PD-1 inhibitors, this study provides evidence on the underlying genetic risk factors and drivers of the disease.
A large-scale study analyzed genetic data from over 17,000 people with hepatocellular carcinoma and more than 2.7 million others. The goal was to find specific genetic markers that might contribute to the development of this type of liver cancer.
The analysis identified 15 specific genetic locations associated with the disease. Among these, three specific variants (MAP3K9, TERT, and GABPB2) were found to act independently of cirrhosis, which is the scarring of the liver. The study also found that some of these genetic markers vary significantly depending on a person's ancestry.
While the study identified 11 potentially causal coding variants, these are not confirmed as the sole cause of the disease. This research is helpful because it identifies specific genetic drivers and risk factors for liver cancer across different ancestral groups. Because these findings are based on large-scale data analysis, they are useful for understanding risk but do not provide a specific diagnosis for individuals.
What this means for you:
Researchers identified 15 genetic locations linked to liver cancer, some of which vary by ancestry.
Common questions
What did the study find regarding genetics and liver cancer?
The study identified 15 genome-wide significant germline loci associated with hepatocellular carcinoma. These include specific areas like GCKR, MTTP, and ADH5. The researchers also identified 11 potentially causal coding variants, such as p.Leu446Pro in GCKR, which may play a role in the condition.
Do these genetic risks depend on liver scarring?
No, the study found that specific variants, including MAP3K9, TERT, and GABPB2, act independently of cirrhosis. This means these particular genetic markers are linked to the risk of liver cancer regardless of whether the liver has developed scarring.
Does the study show different risks for different people?
Yes, the study found significant ancestral heterogeneity in six loci, including the HLA locus. This means that some genetic markers associated with liver cancer vary depending on a person's ancestry, highlighting how genetic risk can differ across different populations.
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) 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.
