Germline ATG7 variants have the potential to impact autophagy, a new study published in Scientific Reports found. This could have implications for the development of cholangiocarcinoma (CCA).

ATG7 is one of the core genes of the autophagy machinery. It is needed for the initiation of autophagy and the formation of the autophagosome.

Here, a team of researchers led by Lincoln D. Nadauld, MD, from the Intermountain Precision Genomics Program at Intermountain Healthcare in Saint George, Utah analyzed a pedigree with familial CCA and found that all members of the family affected by the disease had a novel germline mutation (c.2000C>T p.Arg659*) in the ATG7 gene. 

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Moreover, there were somatic deletions in the gene in the tumors. The researchers demonstrated that the germline mutation and the somatic deletion in the ATG7 gene were found in distinct alleles. Then using a parallel population genetic study, they identified that the germline c.1591C>G p.Asp522Glu polymorphism was associated with a higher risk of CCA.

Read more about the etiology of CCA

The researchers also developed an ATG7-null cell line derived from the human bile duct to understand the effect of these germline variants on autophagy and found that the mutant p.R659* ATG7 protein was not able to lipidate its LC3 substrate. This caused a complete loss of autophagy and led to an increase in the levels of the autophagy receptor protein P62.

“Our findings indicate that germline ATG7 variants have the potential to impact autophagy function with implications for [CCA] development,” they wrote.

The role of autophagy in cancer is not clear but germline mutations in several autophagy genes are known to be implicated in hereditary neurodegenerative and autoimmune diseases. Moreover, single nucleotide polymorphisms in the ATG5 and ATG7 genes have been shown to be associated with clear cell renal cell carcinoma.

The authors of the study said that they will investigate the exact mechanism of how the loss of function of the ATG7 protein leads to tumorigenesis in CCA.


Greer SU, Chen J, Ogmundsdottir MH, et al. Germline variants of ATG7 in familial cholangiocarcinoma alter autophagy and p62. Sci Rep. 2022;12(1):10333. doi:10.1038/s41598-022-13569-4