| Autor: |
Margret H. Ogmundsdottir, Jiamin Chen, Imelda T Sandoval, Richard Glenn C Delacruz, Sigrun Kristjansdottir, Billy T. Lau, David A. Jones, Stephanie U. Greer, John Bell, Lincoln Nadauld, Robin Romero, Jon G. Jonasson, Gail Fulde, Hanlee P. Ji, Derrick S. Haslem, Eiríkur Steingrímsson |
| Rok vydání: |
2019 |
| Předmět: |
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| DOI: |
10.1101/836767 |
| Popis: |
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 ATG7 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, ATG7, and all of the affected individuals had cholangiocarcinoma tumors harboring somatic genomic deletions of ATG7. From a population genetic study, we identified a germline polymorphism of ATG7 (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 ATG7 mutation had functional consequences, we developed an ATG7-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 ATG7. Moreover, in zebrafish embryos depleted of atg7, a reproducible necrotic head phenotype was rescued by injection of wildtype ATG7 but not mutant ATG7. Our findings point to ATG7 as a causative genetic risk factor for cholangiocarcinoma and implicate autophagy as a novel cancer driver mechanism. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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