European Genome-Wide Association Study of Genetic Variants in Alcohol-Related Hepatocellular Carcinoma

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In a case-control genome-wide association study among persons of European ancestry reported in The Lancet Oncology, Trépo et al identified common genetic variants associated with the risk of alcohol-related hepatocellular carcinoma (HCC).

Study Details

The study involved a discovery cohort of 2,107 unrelated European patients with alcohol-related liver disease aged 20 to 92 years, who were recruited between October 1993 and March 2017. Cases were patients with alcohol-related HCC diagnosed by imaging or histology, and controls were patients with alcohol-related liver disease without HCC. New candidate variant associations (at P < 1 × 10−6) and variants previously associated with alcohol-related HCC were assessed in a validation cohort of 1,933 patients with alcohol-related liver disease aged 29 to 92 years recruited between July 1995 and May 2019. 

Key Findings

In an assessment of 7,962,325 variants in the discovery cohort of 775 cases vs 1,332 controls, a significant genome-wide association was found for a new candidate variant in WNT3A-WNT9A (rs708113; P = 1.11 × 10−8) and significant associations were found for previously reported regions associated with alcohol-related HCC risk at TM6SF2 (rs58542926; P = 6.02 × 10−10), PNPLA3 (rs738409; P = 9.29 × 10−7), and HSD17B13 (rs72613567; P = 2.49 × 10−4).

In the validation cohort of 874 cases vs 1,059 controls, significant associations were found for WNT3A-WNT9A (rs708113; P = 1.17 × 10−3), TM6SF2 (rs58542926; P = 4.06 × 10−5), and PNPLA3 (rs738409; P = 1.17 × 10−4).

In a meta-analysis including both cohorts, significant associations for alcohol-related HCC risk were found for WNT3A-WNT9A (odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.66–0.81, P = 3.93 × 10−10), TM6SF2 (OR = 1.77, 95% CI = 1.52–2.07, P = 3.84 ×10−13), and PNPLA3 (OR = 1.34, 95% CI = 1.22–1.47, P = 7.30 × 10−10). An additive effect of risk alleles on risk for alcohol-related HCC was observed. WNT3A-WNT9A rs708113 was not associated with liver fibrosis.

The investigators stated, “We identified a risk locus on chromosome 1 spanning the WNT3A and WNT9A genes both involved in the Wnt–β-catenin pathway. The WNT3A-WNT9A rs708113[T] minor allele mitigated the risk of developing alcohol-related HCC in patients of European ancestry. We also confirmed an association with PNPLA3 and TM6SF2 at the genome-wide level. The protective WNT3A-WNT9A rs708113[T] allele was also associated with STAT3 activation genes in non-tumor liver tissue from alcohol-related HCC. Finally, rs708113[T] was associated with an increased prevalence of immune cells and a lower proportion of CTNNB1 somatic mutations in patients with alcohol-related HCC.”

They concluded, “WNT3A-WNT9A is a susceptibility locus for alcohol-related HCC, suggesting an early role of the Wnt–β-catenin pathway in alcohol-related HCC carcinogenesis.”

Jessica Zucman-Rossi, PhD, of the Centre de recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Ligue Nationale contre le Cancer, Bpifrance, INSERM, AFEF, CARPEM, Labex OncoImmunology, and Agence Nationale de la Recherche. For full disclosures of the study authors, visit