Germline variants of ATG7 in familial cholangiocarcinoma alter autophagy and p62

• Published in: Scientific Reports
• Main Authors: Greer, Stephanie U., Chen, Jiamin, Ogmundsdottir, Margret H., Ayala, Carlos, Lau, Billy T., Delacruz, Richard Glenn C., Sandoval, Imelda T., Jones, David A., Haslem, Derrick S., Romero, Robin, Fulde, Gail, Bell, John M., Jonasson, Jon G., Steingrimsson, Eirikur, Ji, Hanlee P., Nadauld, Lincoln D.
• Other Authors: Faculty of Medicine, Clinical Laboratory Services, Diagnostics and Blood Bank
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2022
• Subjects: Meinafræði; Autophagy-Related Protein 7/genetics; Autophagy/genetics; Bile Duct Neoplasms/genetics; Bile Ducts; Intrahepatic; Cholangiocarcinoma/genetics; Germ Cells/metabolism; Humans; RNA-Binding Proteins/genetics; Iceland
• Online Access: https://hdl.handle.net/20.500.11815/3881; https://doi.org/10.1038/s41598-022-13569-4

Funding Information: The authors recognize and appreciate the patients and families who contributed to the current study. We acknowledge the Icelandic Cancer Registry for assistance in the ascertainment of the Icelandic cancer patients. We thank deCODE genetics for access to data and facilities, assistance with data analysis and helpful discussions. This work was supported by the National Institutes of Health [P01HG000205 to SUG and HPJ, 1U01CA15192001-A1 to HPJ, 1U01CA176299 to HPJ, HG006137-07 to HPJ, R01 CA116468NIH to DAJ, 5K08CA166512 to LDN]; Intermountain Healthcare to SUG, JC and HPJ; a Research Scholar Grant from the American Cancer Society [RSG-13-297-01-TBG to JC and HPJ]; Clayville Foundation to HPJ; Gastric Cancer Foundation to HPJ and LDN; the Samuel Waxman Cancer Research Foundation to DAJ; Oklahoma Center for Adult Stem Cell Research (OCASCR) to DAJ; Oklahoma Medical Research Foundation (OMRF) to DAJ; the Conquer Cancer Foundation (Young Investigator Award) to LDN; the Carl Kawaja Foundation to LDN; the Research Fund of Iceland [130230-0529 to ES and MHO, 184861-052 to ES, 184727-051 to MHO]; and a grant from the Icelandic Cancer Society Research Fund to MHO. Publisher Copyright: © 2022, The Author(s). Autophagy is a housekeeping mechanism tasked with eliminating misfolded proteins and damaged organelles to maintain cellular homeostasis. Autophagy deficiency results in increased oxidative stress, DNA damage and chronic cellular injury. Among the core genes in the autophagy machinery, ATG7 is required for autophagy initiation and autophagosome formation. Based on the analysis of an extended pedigree of familial cholangiocarcinoma, we determined that all affected family members had a novel germline mutation (c.2000C>T p.Arg659* (p.R659*)) in ATG7. Somatic deletions of ATG7 were identified in the tumors of affected individuals. We applied linked-read sequencing to one tumor sample and demonstrated that the ATG7 somatic deletion and germline mutation were located on distinct alleles, resulting ...