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BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

Cholangiocarcinoma is associated with several different risk factors, many of which have known genetic associations. Advances in our understanding of the human genome have translated to the development of gene specific and whole genome assays for identifying gene variants and other alterations associated with cancer development. An improved understanding of the inherited genetic variants associated with risk of cholangiocarcinoma has the potential to improve our understanding of the basic biology of cholangiocarcinoma, enhance the performance of risk stratification models for identifying individuals at highest risk for cholangiocarcinoma, and identifying genetic variants associated with predisposition to cholangiocarcinoma in families with multiple affected individuals. It is increasingly recognized that major cancer-causing mutations or other gene alterations associated with familial risk of multiple cancers can also occur as germline events in individuals with apparently sporadically occurring cancer. In this chapter we review the major risk factors for cholangiocarcinoma as well as known gene variants associated with these risk factors, gene variants that have been associated with cholangiocarcinoma as the result of interrogation of candidate genes known to be associated with putative cancer causing pathways in cholangiocarcinoma, as well as the prevalence of major cancer causing genetic aberrations shown to be inherited in the germline of patients with sporadically developed cholangiocarcinoma. There has not yet been any large-scale genome wide association study of cholangiocarcinoma, and the results from such a study are eagerly anticipated., Competing Interests: Conflict of interest statement M.A.S. has no financial or personal disclosures relevant to the contents of this manuscript. L.R.R. reports grants from NIH (CA186566 and CA210964), Mayo Clinic, The Cholangiocarcinoma Foundation, Bayer, Boston Scientific, Exact Sciences, Fujifilm Medical Sciences, Gilead Sciences, Glycotest Inc., PSC Partners Seeking a Cure, Redhill Biopharma, and TARGET PharmaSolutions during the conduct of the study; other support from MedEd Design LLC, Pontifax, Global Life Science Consulting, The Lynx Group, AstraZeneca, Bayer, Eisai, Exact Sciences, and GRAIL Inc., (Copyright © 2022 Elsevier Inc. All rights reserved.)