Claudio Luchini1,2, Scott A Robertson2, Seung-Mo Hong3, Matthäus Felsenstein2, Robert A Anders2, Antonio Pea4,5, Alessia Nottegar1, Nicola Veronese6,7, Jin He5, Matthew J Weiss5, Paola Capelli1, Aldo Scarpa1,8, Pedram Argani2, Payal Kapur9, Laura D Wood2,10. 1. Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy. 2. Department of Pathology, Johns Hopkins University, Baltimore, MD, USA. 3. Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. 4. Department of Surgery, University and Hospital Trust of Verona, Verona, Italy. 5. Department of Surgery, Johns Hopkins University, Baltimore, MD, USA. 6. National Research Council, Neuroscience Institute, Aging Branch, Padua, Italy. 7. Institute for Clinical Research and Education in Medicine (IREM), Padua, Italy. 8. ARC-Net Research Center, University of Verona, Verona, Italy. 9. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 10. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD, USA.
Abstract
AIMS: Somatic mutations in genes encoding chromatin remodellers have been reported recently in several cancer types, including approximately half of cholangiocarcinomas. One of the most commonly mutated chromatin remodellers in cholangiocarcinoma is the Polybromo-1 (PBRM1) gene located on chromosome 3p21, which encodes a subunit of the SWI/SNF complex. The aim of this study was to determine the timing of PBRM1 mutations in biliary carcinogenesis. METHODS AND RESULTS: In order to accomplish this goal, 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 tumour suppressor gene. We found that PBRM1 loss occurred in approximately 26% of invasive cancers, but PBRM1 expression was retained in all biliary intra-epithelial neoplasia (BilIN) specimens, including 25 intrahepatic BilINs and 19 gallbladder BilINs. CONCLUSIONS: These findings indicate that PBRM1 mutation (and resultant loss of expression) is a late event during biliary carcinogenesis. In addition, we confirm a lack of prognostic significance of PBRM1 status in invasive intrahepatic cholangiocarcinoma. This study provides important insights into the basic mechanisms of chromatin remodelling genes in carcinogenesis.
AIMS: Somatic mutations in genes encoding chromatin remodellers have been reported recently in several cancer types, including approximately half of cholangiocarcinomas. One of the most commonly mutated chromatin remodellers in cholangiocarcinoma is the Polybromo-1 (PBRM1) gene located on chromosome 3p21, which encodes a subunit of the SWI/SNF complex. The aim of this study was to determine the timing of PBRM1 mutations in biliary carcinogenesis. METHODS AND RESULTS: In order to accomplish this goal, 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 tumour suppressor gene. We found that PBRM1 loss occurred in approximately 26% of invasive cancers, but PBRM1 expression was retained in all biliary intra-epithelial neoplasia (BilIN) specimens, including 25 intrahepaticBilINs and 19 gallbladder BilINs. CONCLUSIONS: These findings indicate that PBRM1 mutation (and resultant loss of expression) is a late event during biliary carcinogenesis. In addition, we confirm a lack of prognostic significance of PBRM1 status in invasive intrahepatic cholangiocarcinoma. This study provides important insights into the basic mechanisms of chromatin remodelling genes in carcinogenesis.
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