Header

UZH-Logo

Maintenance Infos

Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma


Bihr, Svenja; Ohashi, Riuko; Moore, Ariane L; Rüschoff, Jan H; Beisel, Christian; Hermanns, Thomas; Mischo, Axel; Corrò, Claudia; Beyer, Jörg; Beerenwinkel, Niko; Moch, Holger; Schraml, Peter (2019). Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma. Neoplasia, 21(2):247-256.

Abstract

Bi-allelic inactivation of the VHL gene on chromosome 3p is the characteristic feature in most clear cell renal cell carcinomas (ccRCC). Frequent gene alterations were also identified in SETD2, BAP1 and PBRM1, all of which are situated on chromosome 3p and encode histone/chromatin regulators. The relationship between gene mutation, loss of protein expression and the correlations with clinicopathological parameters is important for the understanding of renal cancer progression. We analyzed PBRM1 and BAP1 protein expression as well as the tri-methylation state of H3K36 as a surrogate marker for SETD2 activity in more than 700 RCC samples. In ccRCC loss of nuclear PBRM1 (68%), BAP1 (40%) and H3K36me3 (47%) expression was significantly correlated with each other, advanced tumor stage, poor tumor differentiation (P < .0001 each), and necrosis (P < .005) Targeted next generation sequencing of 83 ccRCC samples demonstrated a significant association of genetic mutations in PBRM1, BAP1, and SETD2 with absence of PBRM1, BAP1, and HEK36me3 protein expression (P < .05, each). By assigning the protein expression patterns to evolutionary subtypes, we revealed similar clinical phenotypes as suggested by TRACERx Renal. Given their important contribution to tumor suppression, we conclude that combined functional inactivation of PBRM1, BAP1, SETD2 and pVHL is critical for ccRCC progression.

Abstract

Bi-allelic inactivation of the VHL gene on chromosome 3p is the characteristic feature in most clear cell renal cell carcinomas (ccRCC). Frequent gene alterations were also identified in SETD2, BAP1 and PBRM1, all of which are situated on chromosome 3p and encode histone/chromatin regulators. The relationship between gene mutation, loss of protein expression and the correlations with clinicopathological parameters is important for the understanding of renal cancer progression. We analyzed PBRM1 and BAP1 protein expression as well as the tri-methylation state of H3K36 as a surrogate marker for SETD2 activity in more than 700 RCC samples. In ccRCC loss of nuclear PBRM1 (68%), BAP1 (40%) and H3K36me3 (47%) expression was significantly correlated with each other, advanced tumor stage, poor tumor differentiation (P < .0001 each), and necrosis (P < .005) Targeted next generation sequencing of 83 ccRCC samples demonstrated a significant association of genetic mutations in PBRM1, BAP1, and SETD2 with absence of PBRM1, BAP1, and HEK36me3 protein expression (P < .05, each). By assigning the protein expression patterns to evolutionary subtypes, we revealed similar clinical phenotypes as suggested by TRACERx Renal. Given their important contribution to tumor suppression, we conclude that combined functional inactivation of PBRM1, BAP1, SETD2 and pVHL is critical for ccRCC progression.

Statistics

Citations

Dimensions.ai Metrics
18 citations in Web of Science®
19 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

13 downloads since deposited on 25 Jul 2019
12 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology and Hematology
04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > University Hospital Zurich > Urological Clinic
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Cancer Research
Language:English
Date:February 2019
Deposited On:25 Jul 2019 10:22
Last Modified:01 Oct 2020 15:21
Publisher:Neoplasia Press
ISSN:1476-5586
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.neo.2018.12.006
PubMed ID:30660076

Download

Gold Open Access

Download PDF  'Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma'.
Preview
Content: Published Version
Filetype: PDF
Size: 2MB
View at publisher
Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)