Rs708113 in WNT3A-WNT9A and hepatocellular carcinoma risk

Hepatocellular carcinoma is the most frequent primary liver malignancy and fourth most common cause of cancer-related mortality worldwide. 1 Global Burden of Disease Cancer CollaborationGlobal, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol. 2017; 3: 524-548 Crossref PubMed Scopus (2549) Google Scholar Although chronic viral hepatitis, particularly due to hepatitis B virus (HBV) infection, is the most common underlying liver disease leading to hepatocellular carcinoma in southeast Asia, alcohol-related liver disease and non-alcoholic fatty liver disease are the predominant causes in Europe and North America. Alcohol-related liver disease and non-alcoholic fatty liver disease are expected to become the leading causes of hepatocellular carcinoma in the future, with HBV and hepatitis C virus infections declining as a result of effective vaccination strategies and treatments. With few exceptions, most hepatocellular carcinoma cases in high-income countries develop in patients with established cirrhosis; alcohol-related cirrhosis is the second most common risk factor for hepatocellular carcinoma in high-income countries, 2 West J Card TR Aithal GP Fleming KM Risk of hepatocellular carcinoma among individuals with different aetiologies of cirrhosis: a population-based cohort study. Aliment Pharmacol Ther. 2017; 45: 983-990 Crossref PubMed Scopus (40) Google Scholar with an annual risk of hepatocellular carcinoma of up to 2·5%. 3 Mancebo A González-Diéguez ML Cadahía V et al. Annual incidence of hepatocellular carcinoma among patients with alcoholic cirrhosis and identification of risk groups. Clin Gastroenterol Hepatol. 2013; 11: 95-101 Summary Full Text Full Text PDF PubMed Scopus (108) Google Scholar Alcohol-related hepatocellular carcinoma is a complex disease, but easily discernible clinical risk factors include type 2 diabetes, obesity, and older age. 4 Llovet JM Kelley RK Villanueva A et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021; 7: 6 Crossref PubMed Scopus (708) Google Scholar Sequence variations in specific genes that modify the risk of alcohol-related hepatocellular carcinoma have been identified, mostly by means of candidate gene case-control studies, which either enhance or alleviate the risk of developing hepatocellular carcinoma. However, the genetic risk loci recognised until now only represent a fraction of the heritability risk, suggesting that additional genetic modulators might exist. 5 Stickel F Buch S Nischalke HD et al. Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis. Am J Gastroenterol. 2018; 113: 1475-1483 Crossref PubMed Scopus (56) Google Scholar The involvement of the rs738409 locus (in the gene coding for PNPLA3) is widely supported by numerous case-control studies, which show the largest effect size among all previously identified genetic risk variants. Additional loci in genes coding for TM6SF2 (rs58542926) and HSD17B13 (rs72613567:TA) were found to increase and alleviate the risk of hepatocellular carcinoma, respectively. 5 Stickel F Buch S Nischalke HD et al. Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis. Am J Gastroenterol. 2018; 113: 1475-1483 Crossref PubMed Scopus (56) Google Scholar , 6 Stickel F Lutz P Buch S et al. Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers. Hepatology. 2020; 72: 88-102 Crossref PubMed Scopus (52) Google Scholar However, unlike in viral hepatitis-associated hepatocellular carcinoma, 7 Jiang DK Sun J Cao G et al. Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma. Nat Genet. 2013; 45: 72-75 Crossref PubMed Scopus (242) Google Scholar , 8 Kumar V Kato N Urabe Y et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet. 2011; 43: 455-458 Crossref PubMed Scopus (303) Google Scholar a comprehensive and hypothesis-free genome-wide study to detect risk loci that might have remained unidentified for alcohol-related hepatocellular carcinoma so far has been lacking. Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association studyWNT3A-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. Full-Text PDF