PBRM1 loss is a late event during the development of cholangiocarcinoma

Claudio Luchini, Scott A. Robertson, Seung Mo Hong, Matthäus Felsenstein, Robert A Anders, Antonio Pea, Alessia Nottegar, Nicola Veronese, Jin He, Matthew J Weiss, Paola Capelli, Aldo Scarpa, Pedram Argani, Payal Kapur, Laura Delong Wood

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)375-382
Number of pages8
JournalHistopathology
Volume71
Issue number3
DOIs
StatePublished - Sep 1 2017

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Cholangiocarcinoma
Bile Pigments
Carcinogenesis
Mutation
Chromatin
Immunohistochemistry
Genes
Neoplasms
Chromatin Assembly and Disassembly
Gallbladder
Tumor Suppressor Genes
Proteins
Chromosomes
Carcinoma

Keywords

  • biliary dysplasia
  • BilIN
  • cholangiocarcinoma
  • chromatin remodelling
  • PBRM1

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology

Cite this

PBRM1 loss is a late event during the development of cholangiocarcinoma. / Luchini, Claudio; Robertson, Scott A.; Hong, Seung Mo; Felsenstein, Matthäus; Anders, Robert A; Pea, Antonio; Nottegar, Alessia; Veronese, Nicola; He, Jin; Weiss, Matthew J; Capelli, Paola; Scarpa, Aldo; Argani, Pedram; Kapur, Payal; Wood, Laura Delong.

In: Histopathology, Vol. 71, No. 3, 01.09.2017, p. 375-382.

Research output: Contribution to journalArticle

Luchini, C, Robertson, SA, Hong, SM, Felsenstein, M, Anders, RA, Pea, A, Nottegar, A, Veronese, N, He, J, Weiss, MJ, Capelli, P, Scarpa, A, Argani, P, Kapur, P & Wood, LD 2017, 'PBRM1 loss is a late event during the development of cholangiocarcinoma', Histopathology, vol. 71, no. 3, pp. 375-382. https://doi.org/10.1111/his.13234
Luchini C, Robertson SA, Hong SM, Felsenstein M, Anders RA, Pea A et al. PBRM1 loss is a late event during the development of cholangiocarcinoma. Histopathology. 2017 Sep 1;71(3):375-382. https://doi.org/10.1111/his.13234
Luchini, Claudio ; Robertson, Scott A. ; Hong, Seung Mo ; Felsenstein, Matthäus ; Anders, Robert A ; Pea, Antonio ; Nottegar, Alessia ; Veronese, Nicola ; He, Jin ; Weiss, Matthew J ; Capelli, Paola ; Scarpa, Aldo ; Argani, Pedram ; Kapur, Payal ; Wood, Laura Delong. / PBRM1 loss is a late event during the development of cholangiocarcinoma. In: Histopathology. 2017 ; Vol. 71, No. 3. pp. 375-382.
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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.",
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