Genome-wide meta-analysis identifies nine loci associated with higher risk of hepatocellular carcinoma development

The genetic underpinnings of hepatocellular carcinoma (HCC) remain largely unknown. Thus, we aimed to identify new genetic risk loci for HCC.

We performed a genome-wide association study (GWAS) meta-analysis of 11 cohorts with validation in two independent cohorts. The identified variants were tested for effects on other hepatobiliary endpoints, and on incident HCC stratified by underlying risk factors. Mendelian randomization was used to assess the causal effects of a range of traits on the risk of HCC.

In meta-analyses totaling 6,540 cases and 2,096,759 controls, we identified 10 associations with HCC, of which five (in KLF15, HSD17B13, APOE, HFE, and MTARC1) have not previously been implicated in HCC at genome-wide statistical significance. Known associations in PNPLA3, TM6SF2, TERT, IFNL4, and HLA-DP1 were confirmed. All associations except KLF15 were validated in independent cohorts totaling 7,630 cases and 733,689 controls. The largest per-allele effect was seen for TM6SF2 (beta = 0.61) followed by PNPLA3 (0.55), HFE (0.45), IFNL4 (0.31), APOE (0.27), HSD17B13, HLA-DP1, and TERT (all 0.21), and MTARC1 (0.17). The identified variants had comparable effects on incident HCC in individuals with prevalent obesity, a high alcohol intake, diabetes, or cirrhosis. Mendelian randomization analyses confirmed the causal role of obesity in HCC. We found strong correlations between genetic effects on HCC and hepatic steatosis (r² = 0.75), and HCC and cirrhosis (r² = 0.69), whereas only three loci (APOE, HFE, and TERT) had concordant effects on HCC and biliary tract cancer.

We identified and validated nine genetic variants associated with an increased risk of HCC development.

The genetic underpinnings of HCC remain largely unknown. In this genome-wide association meta-analysis totaling 6,540 cases with HCC and 2.1 million controls, we identified and validated nine genetic loci to associate with the risk of HCC. A deeper insight into genetic factors that affect the risk of HCC could improve our ability to predict and ultimately prevent or treat this deadly cancer.