PBRM1 loss is a late event during the development of cholangiocarcinoma

Abstract

Somatic mutations in genes encoding chromatin remodelers have been recently reported in several cancer types, including approximately half of cholangiocarcinomas. One of the most commonly mutated chromatin remodelers in cholangiocarcinoma is the PBRM1 gene located on chromosome 3p21, which encodes a subunit of the SWI/SNF complex. In order to determine the timing of PBRM1 mutations in biliary carcinogenesis, we used immunohistochemistry to assess PBRM1 protein expression in a series of precursor lesions and invasive biliary carcinomas. Previous studies have correlated loss of protein expression on immunohistochemistry with inactivating mutations in this tumor suppressor gene. We found that PBRM1 loss occurred in approximately 26% of invasive cancers, but PBRM1 expression was retained in all biliary intraepithelial neoplasia (BilIN) specimens, including 25 intrahepatic BilINs and 19 gallbladder BilINs. These findings indicate that PBRM1 mutation (and resultant loss of expression) is a late event during biliary carcinogenesis. In addition, we also confirm a lack of prognostic significance of PBRM1 status in invasive intrahepatic cholangiocarcinoma. This study provides important insights into the basic mechanisms of chromatin remodeling genes in carcinogenesis.

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