Genetic risk of cholangiocarcinoma is linked to the autophagy gene ATG7

Cholangiocarcinoma is an aggressive cancer originating from the bile duct. Although cholangiocarcinoma does occur in families, to date no specific causative gene has been identified. We identified as a cancer susceptibility gene using a joint genetic analysis of an extended pedigree with familial cholangiocarcinoma in combination with a population genetic association study. Affected family members had a germline mutation (c.2000C>T [p.Arg659*]) in the autophagy related gene, , and all of the affected individuals had cholangiocarcinoma tumors harboring somatic genomic deletions of . From a population genetic study, we identified a germline polymorphism of (c.1591C>G [p.Asp522Glu]) associated with increased risk of cholangiocarcinoma. The autophagy substrate p62 demonstrated a higher accumulation in tumors of p.Asp522Glu carriers compared with non-carriers indicating defective autophagy. To determine whether the germline mutation had functional consequences, we developed an -deficient cholangiocyte cell line, derived from human bile duct, to test for autophagy-mediated lipidation activity. The germline mutation from the familial cholangiocarcinoma demonstrated a lack of lipidation activity compared to the wildtype . Moreover, in zebrafish embryos depleted of , a reproducible necrotic head phenotype was rescued by injection of wildtype but not mutant . Our findings point to as a causative genetic risk factor for cholangiocarcinoma and implicate autophagy as a novel cancer driver mechanism.