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Mutations in KRAS and ARID1a and the Growth of Bile Duct Cancer

By: Kayci Reyer
Posted: Wednesday, January 4, 2023

Research presented in Cell Reports suggests that gene mutations may impact the development of cholangiocarcinoma. The cooperation of mutated KRAS and ARID1A genes appears to prevent tumor suppressor activity and contribute to disease proliferation.

“The identification of ARID1A as critical to the function of the TGF-β–Smad pathway in biliary cells and that ARID1A suppresses [cholangiocarcinoma] offers insight into the epidemiologic finding that mutations in this pathway are enriched in [cholangiocarcinomas] arising in the settings of primary biliary injury when TGF-β–Smad is likely to function to restrain biliary carcinogenesis,” concluded Aram F. Hezel, MD, of the Wilmot Cancer Institute, University of Rochester Medical Center, New York, and colleagues.

The study evaluated hepatocyte and biliary-specific lineage tracing performed in mice. These models indicated that the joint presence of mutated KRAS and ARID1A genes prompted the development of cholangiocarcinoma as well as the creation of tumor progenitors within the biliary compartment. Cells with KRAS and ARID1A mutations were observed to experience rapid proliferation with a disregard for normal cell-control cycles and senescence. The study authors believe this response is associated with the TGF-β–Smad tumor suppressor pathway’s failure to activate.

“It will be important to understand whether manipulation of the TGF-β axis could offer a therapeutic strategy in advanced human [cholangiocarcinomas] that harbor ARID1A mutations,” noted the authors.

Disclosure: For full disclosures of the study authors, visit

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