PBRM1 loss is a late event during the development of cholangiocarcinoma - PubMed (original) (raw)

. 2017 Sep;71(3):375-382.

doi: 10.1111/his.13234. Epub 2017 Jun 22.

Scott A Robertson 2, Seung-Mo Hong 3, Matthäus Felsenstein 2, Robert A Anders 2, Antonio Pea 4 5, Alessia Nottegar 1, Nicola Veronese 6 7, Jin He 5, Matthew J Weiss 5, Paola Capelli 1, Aldo Scarpa 1 8, Pedram Argani 2, Payal Kapur 9, Laura D Wood 2 10

Affiliations

PBRM1 loss is a late event during the development of cholangiocarcinoma

Claudio Luchini et al. Histopathology. 2017 Sep.

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.

Keywords: BilIN; PBRM1; biliary dysplasia; cholangiocarcinoma; chromatin remodelling.

© 2017 John Wiley & Sons Ltd.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

LDW is a paid consultant for Personal Genome Diagnostics. All the other authors have no potential conflict of interest.

Figures

Figure 1

Figure 1

BilINs in liver and gallbladder (H&E images). A. Intrahepatic BilIN-1. B. Intrahepatic BilIN-2. C. Intrahepatic BilIN-3. D. Gallbladder BilIN-1. E. Gallbladder BilIN-2. F. Gallbladder BilIN-3.

Figure 1

Figure 1

BilINs in liver and gallbladder (H&E images). A. Intrahepatic BilIN-1. B. Intrahepatic BilIN-2. C. Intrahepatic BilIN-3. D. Gallbladder BilIN-1. E. Gallbladder BilIN-2. F. Gallbladder BilIN-3.

Figure 1

Figure 1

BilINs in liver and gallbladder (H&E images). A. Intrahepatic BilIN-1. B. Intrahepatic BilIN-2. C. Intrahepatic BilIN-3. D. Gallbladder BilIN-1. E. Gallbladder BilIN-2. F. Gallbladder BilIN-3.

Figure 1

Figure 1

BilINs in liver and gallbladder (H&E images). A. Intrahepatic BilIN-1. B. Intrahepatic BilIN-2. C. Intrahepatic BilIN-3. D. Gallbladder BilIN-1. E. Gallbladder BilIN-2. F. Gallbladder BilIN-3.

Figure 1

Figure 1

BilINs in liver and gallbladder (H&E images). A. Intrahepatic BilIN-1. B. Intrahepatic BilIN-2. C. Intrahepatic BilIN-3. D. Gallbladder BilIN-1. E. Gallbladder BilIN-2. F. Gallbladder BilIN-3.

Figure 1

Figure 1

BilINs in liver and gallbladder (H&E images). A. Intrahepatic BilIN-1. B. Intrahepatic BilIN-2. C. Intrahepatic BilIN-3. D. Gallbladder BilIN-1. E. Gallbladder BilIN-2. F. Gallbladder BilIN-3.

Figure 2

Figure 2

Immunohistochemistry for PBRM1 in dysplastic and malignant biliary lesions. A. Intrahepatic cholangiocarcinoma with retained nuclear PBRM1 expression. B. Intrahepatic cholangiocarcinoma with loss of nuclear PBRM1. This expression pattern is correlated with mutations in the PBRM1 gene. C. BilIN with retained nuclear PBRM1 expression. No BilIN lesions showed loss of nuclear PBRM1 expression.

Figure 2

Figure 2

Immunohistochemistry for PBRM1 in dysplastic and malignant biliary lesions. A. Intrahepatic cholangiocarcinoma with retained nuclear PBRM1 expression. B. Intrahepatic cholangiocarcinoma with loss of nuclear PBRM1. This expression pattern is correlated with mutations in the PBRM1 gene. C. BilIN with retained nuclear PBRM1 expression. No BilIN lesions showed loss of nuclear PBRM1 expression.

Figure 2

Figure 2

Immunohistochemistry for PBRM1 in dysplastic and malignant biliary lesions. A. Intrahepatic cholangiocarcinoma with retained nuclear PBRM1 expression. B. Intrahepatic cholangiocarcinoma with loss of nuclear PBRM1. This expression pattern is correlated with mutations in the PBRM1 gene. C. BilIN with retained nuclear PBRM1 expression. No BilIN lesions showed loss of nuclear PBRM1 expression.

Figure 3

Figure 3

Intracystic papillary neoplasm with focal PBRM1 loss. This lesions showed both low-grade dysplasia (A.) and high-grade dysplasia (B.). In the areas of low-grade dysplasia, PBRM1 expression was retained (C.), while expression of PBRM1 was lost in an area with high-grade dysplasia (D.).

Figure 3

Figure 3

Intracystic papillary neoplasm with focal PBRM1 loss. This lesions showed both low-grade dysplasia (A.) and high-grade dysplasia (B.). In the areas of low-grade dysplasia, PBRM1 expression was retained (C.), while expression of PBRM1 was lost in an area with high-grade dysplasia (D.).

Figure 3

Figure 3

Intracystic papillary neoplasm with focal PBRM1 loss. This lesions showed both low-grade dysplasia (A.) and high-grade dysplasia (B.). In the areas of low-grade dysplasia, PBRM1 expression was retained (C.), while expression of PBRM1 was lost in an area with high-grade dysplasia (D.).

Figure 3

Figure 3

Intracystic papillary neoplasm with focal PBRM1 loss. This lesions showed both low-grade dysplasia (A.) and high-grade dysplasia (B.). In the areas of low-grade dysplasia, PBRM1 expression was retained (C.), while expression of PBRM1 was lost in an area with high-grade dysplasia (D.).

Figure 4

Figure 4

Kaplan-Meier curves showing the survival of ICC patients categorized by PBRM1 expression (dark grey: PBRM1 loss; light grey: PBRM1 retained). The overall survival is not significantly different between these two groups.

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