Mutations in SMAD4 and PBRM1 as well as a history of biliary surgery are all independent protective factors for metastasis in advanced cholangiocarcinoma (CCA), according to a new study published in the Journal of International Medical Research.

The researchers also found that TP53 mutations were significantly more frequent in extrahepatic CCA and that mutations in ARID1A were more frequent in intrahepatic CCA.

“Research into the tumor microenvironment and the function of various mutations aims to improve patient survival times and quality of life by enabling the targeted treatment of tumors,” the authors wrote.

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“The six most commonly mutated genes in CCA were investigated for mutation frequency between patients with [extrahepatic CCA] and those with [intrahepatic CCA]: TP53, ARID1A, KRAS, cyclin dependent kinase inhibitor (CDKN)2A, SMAD family member (SMAD)4, and polybromo (PBRM)1.”

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The research team conducted a retrospective study of 91 patients aged 30 to 78 years with advanced CCA at a single center in China between January 2017 and December 2019. They performed comprehensive genomic alteration analyses of tumor samples using an assay panel of genes related to cancer as well as specific introns of genes that are often rearranged in cancer.

The results showed that the mutation frequencies of the 6 genes did not significantly differ between subgroups. However, SMAD4 and PBRM1 were found significantly less often in patients with metastasis. Univariate analysis showed that having a history of biliary surgery was also protective against metastasis in CCA.

The authors caution that the exact nature of the mutations was not determined, nor could the presence of activating mutations or interactions with other genes be ruled out; therefore future studies are warranted to explore these issues.


Song H, Huang Y, Jiang X. Mutation spectrum associated with metastasis of advanced cholangiocarcinoma. J Int Med Res. Published online June 21, 2022. doi:10.1177/03000605221102080