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Germline variants of ATG7 in familial cholangiocarcinoma alter autophagy and p62

Germline variants of ATG7 in familial cholangiocarcinoma alter autophagy and p62


Title: Germline variants of ATG7 in familial cholangiocarcinoma alter autophagy and p62
Author: Greer, Stephanie U.
Chen, Jiamin
Ogmundsdottir, Margret H.
Ayala, Carlos
Lau, Billy T.
Delacruz, Richard Glenn C.
Sandoval, Imelda T.
Kristjansdottir, Sigrun
Jones, David A.
Haslem, Derrick S.
... 7 more authors Show all authors
Date: 2022-06-20
Language: English
Scope: 10333
University/Institute: The Árni Magnússon Institute for Icelandic Studies
Department: Faculty of Medicine
Clinical Laboratory Services, Diagnostics and Blood Bank
Series: Scientific Reports; 12(1)
ISSN: 2045-2322
DOI: https://doi.org/10.1038/s41598-022-13569-4
Subject: Autophagy-Related Protein 7/genetics; Autophagy/genetics; Bile Duct Neoplasms/genetics; Bile Ducts, Intrahepatic; Cholangiocarcinoma/genetics; Germ Cells/metabolism; Humans; RNA-Binding Proteins/genetics
URI: https://hdl.handle.net/20.500.11815/3881

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Citation:

Greer , S U , Chen , J , Ogmundsdottir , M H , Ayala , C , Lau , B T , Delacruz , R G C , Sandoval , I T , Kristjansdottir , S , Jones , D A , Haslem , D S , Romero , R , Fulde , G , Bell , J M , Jonasson , J G , Steingrimsson , E , Ji , H P & Nadauld , L D 2022 , ' Germline variants of ATG7 in familial cholangiocarcinoma alter autophagy and p62 ' , Scientific Reports , vol. 12 , no. 1 , 10333 , pp. 10333 . https://doi.org/10.1038/s41598-022-13569-4

Abstract:

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 in two hits to ATG7. From a parallel population genetic study, we identified a germline polymorphism of ATG7 (c.1591C>G p.Asp522Glu (p.D522E)) associated with increased risk of cholangiocarcinoma. To characterize the impact of these germline ATG7 variants on autophagy activity, we developed an ATG7-null cell line derived from the human bile duct. The mutant p.R659* ATG7 protein lacked the ability to lipidate its LC3 substrate, leading to complete loss of autophagy and increased p62 levels. Our findings indicate that germline ATG7 variants have the potential to impact autophagy function with implications for cholangiocarcinoma development.

Description:

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).

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