肝细胞癌是酒精相关性肝病的常见后果，在重度饮酒者中发病率不同。我们进行了一项全基因组关联研究（GWAS），以确定酒精相关肝细胞癌的常见遗传变异。
我们在1993年10月22日至2017年3月12日招募的2107名年龄20-92岁的非相关欧洲酒精相关性肝病患者的发现队列中进行了两阶段病例对照GWAS。病例为通过影像学或组织学诊断的酒精相关性肝细胞癌患者。对照组为无肝细胞癌的酒精相关性肝病患者。我们使用加性逻辑回归模型调整了前十个主成分，以评估与酒精相关的肝细胞癌相关的遗传变异。我们做了另一个调整年龄的分析，性别,和肝纤维化。在1995年7月21日招募的1933名年龄29-92岁的酒精相关性肝病患者的验证队列中，评估了新的候选关联（p<1×10-6）和以前与酒精相关性肝细胞癌相关的变异，2019年5月2日。我们对两个病例对照队列进行了荟萃分析。
发现队列包括775例病例和1332例对照。在评估的7962325种变体中，我们确定了WNT3A-WNT9A（rs708113;p=1·11×10-8），并在TM6SF2（rs58542926;p=6·02×10-10）发现了先前报道的与酒精相关肝细胞癌风险相关的区域的支持，PNPLA3(rs738409;p=9·29×10-7),和HSD17B13(rs72613567;p=2·49×10-4)。验证队列包括874例病例和1059例对照，复制了三个变体：WNT3A-WNT9A（rs708113;p=1·17×10-3），TM6SF2(rs58542926；p=4·06×10-5)，和PNPLA3(rs738409;p=1·17×10-4)。在荟萃分析中，所有三种变体均达到GWAS的显著性：WNT3A-WNT9A（比值比0·73，95％CI0·66-0·81；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）。对临床协变量的调整产生了类似的结果。我们观察到风险等位基因对酒精相关肝细胞癌的累加效应。WNT3A-WNT9Ars708113与肝纤维化无关。
WNT3A-WNT9A是酒精相关性肝细胞癌的易感位点，提示Wnt-β-catenin通路在酒精相关性肝细胞癌变中的早期作用。
LigueNationaleContreleCancer,Bpifrance,INSERM,AFEF,Carpem,Labex肿瘤免疫学,和国家机构。
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.
