Abstract
Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma. We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20-92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (p<1 × 10-6) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29-92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case-control cohorts. The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10-8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10-10), PNPLA3 (rs738409; p=9·29 × 10-7), and HSD17B13 (rs72613567; p=2·49 × 10-4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10-3), TM6SF2 (rs58542926; p=4·06 × 10-5), and PNPLA3 (rs738409; p=1·17 × 10-4). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66-0·81; p=3·93 × 10-10), TM6SF2 (1·77, 1·52-2·07; p=3·84×10-13), PNPLA3 (1·34, 1·22-1·47; p=7·30 × 10-10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis. WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt-β-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis. Ligue Nationale contre le Cancer, Bpifrance, INSERM, AFEF, CARPEM, Labex OncoImmunology, and Agence Nationale de la Recherche.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third most common cause of cancer-related death.[1]
Several clinical features have been identified in cohort studies as risk factors for alcohol-related HCC and include older age, male sex, and liver fibrosis with most cases developing at cirrhosis stage.[1]
We performed a genome-wide association studies (GWAS) in patients with Alcohol-related liver disease (ALD) to better delineate the contribution of common genetic variations to the risk of alcohol-related HCC and signaling pathways driving alcohol-related hepatocarcinogenesis
Summary
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third most common cause of cancer-related death.[1]. Carriage of rs738409[G] and rs58542926[T] increases the risk of alcohol-related HCC.[5,6] Of note, both variants were initially identified by independent GWAS in the settings of the presence of nonalcoholic fatty liver disease (NAFLD)[7,8] and alcohol-related cirrhosis.[9] Functional exploration of PNPLA3 rs738409(C>G) and TM6SF2 rs58542926(C>T) - both involved in lipid turnover - has markedly contributed to a better understanding of fatty liver disease pathobiology.[10] their precise roles in the accumulation of liver fibrosis and, alcohol-related hepatocarcinogenesis - through potential direct oncogenic mechanisms - remain unknown.[10] More recently, an association between a variant, rs72613567(T>TA) in HSD17B13, and steatosis/cirrhosis in ALD and NAFLD was identified by another GWAS.[11] Follow-up candidate gene studies reported that rs72613567[TA] decreased the risk of alcohol-related HCC but the effect appears to be much milder than variations in PNPLA3 and TM6SF212. We performed a GWAS in patients with ALD to better delineate the contribution of common genetic variations to the risk of alcohol-related HCC and signaling pathways driving alcohol-related hepatocarcinogenesis
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