Genetic risk of cholangiocarcinoma is linked to the autophagy gene ATG7

Abstract

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 noncarriers 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 headphenotype 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.

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

“…In CCA, several pieces of evidence strongly suggest a deregulated autophagy at the initial steps of cholangiocarcinogenesis, where defective autophagy would allow oncogenic transformation. Supporting this theory, Greer et al showed a genetic risk of CCA linked to ATG7 deficiency and therefore autophagy impairment, mediated by a lack of lipidation activity and p62 accumulation compared with wild-type ATG7 carriers [33]. Moreover, precursor BilIN lesions showed higher levels of LC3-II and p62 compared with normal biliary ducts [105], indicative of uncomplete autophagic process, reinforcing the theory of autophagy inhibition as a contributor to carcinogenic transformation.…”

“…Based on nomograms, they stratified iCCA patients and generated a therapeutic strategy after hepatectomy, demonstrating that nomograms based on autophagy markers can be considered as effective models to predict postoperative survival of iCCA patients [31]. In a very interesting study published in 2019, Atg7 was found to be a causative genetic risk factor for CCA development in a family with a high incidence of pCCA, identifying a germline mutation associated with CCA development [33]. This genetic variant resulted in the accumulation of p62, indicative of impaired autophagy in the tumors of carriers compared with noncarrier tumors, confirming autophagy pathway perturbation as a novel cancer driver mechanism in human tumorigenesis in correlation with the detection of impaired autophagy in BilIN lesions [105].…”

“…Autophagy has been shown to act as a tumor promoter as well as a tumor suppressor in cancer, depending on the cell context, and autophagy modulation has arisen as a promising therapeutic strategy to treat cancer [20][21][22][23][24][25]. Even though the molecular mechanisms of autophagy regulation of tumor biology are not fully understood, multiple reports are showing promising therapeutic potential in combination with other drugs, such as chemotherapy [26].In CCA, several reports released during the last decades have shown how autophagy deregulation is associated with malignant cells compared with normal cholangiocytes in clinical samples, correlating with metastatic disease and poor prognosis [27][28][29][30][31][32][33], and how autophagy modulation shows anticancer efficacy in preclinical models.This review collects clinical and preclinical scientific reports involving autophagy modulation in CCA, putting all puzzle pieces together to try to shed light on the current knowledge of this therapeutic strategy for treating this aggressive disease.…”

“…In CCA, several reports released during the last decades have shown how autophagy deregulation is associated with malignant cells compared with normal cholangiocytes in clinical samples, correlating with metastatic disease and poor prognosis [27][28][29][30][31][32][33], and how autophagy modulation shows anticancer efficacy in preclinical models.…”

Emerging roles of ATG7 in human health and disease

“…In humans, the link between ATG7 dysfunction and cancer formation is only starting to emerge. Recently, familial cholangiocarcinoma (an aggressive cancer of the bile duct) has been associated with ATG7 mutations (preprint: Greer et al , 2019 ). In this study, a number of individuals harbouring inherited monoallelic ATG7 variants (interestingly including the p.Arg659* (NP_ 006386.1) variant identified in Family 1 (Collier et al , 2021 )) were discovered having developed cholangiocarcinoma.…”