Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation

Payal Kapur; Samuel Peña-Llopis; Alana Christie; Leah Zhrebker; Andrea Pavía-Jiménez; W Kimryn Rathmell; Xian-Jin Xie; James Brugarolas

doi:10.1016/S1470-2045(12)70584-3

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Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation

Journal article

Peer reviewed

Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation

Payal Kapur, Samuel Peña-Llopis, Alana Christie, Leah Zhrebker, Andrea Pavía-Jiménez, W Kimryn Rathmell, Xian-Jin Xie and James Brugarolas

The lancet oncology, Vol.14(2), pp.159-167

02/2013

DOI: 10.1016/S1470-2045(12)70584-3

PMCID: PMC4674067

PMID: 23333114

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Abstract

Clear-cell renal-cell carcinomas display divergent clinical behaviours. However, the molecular genetic events driving these behaviours are unknown. We discovered that BAP1 is mutated in about 15% of clear-cell renal-cell carcinoma, and that BAP1 and PBRM1 mutations are largely mutually exclusive. The aim of this study was to investigate the clinicopathological significance of these molecular subtypes and to determine whether patients with BAP1-mutant and PBRM1-mutant tumours had different overall survival. In this retrospective analysis, we assessed 145 patients with primary clear-cell renal-cell carcinoma and defined PBRM1 and BAP1 mutation status from the University of Texas Southwestern Medical Center (UTSW), TX, USA, between 1998 and 2011. We classified patients into those with BAP1-mutant tumours and those with tumours exclusively mutated for PBRM1 (PBRM1-mutant). We used a second independent cohort (n=327) from The Cancer Genome Atlas (TCGA) for validation. In both cohorts, more than 80% of patients had localised or locoregional disease at presentation. Overall both cohorts were similar, although the TCGA had more patients with metastatic and higher-grade disease, and more TCGA patients presented before molecularly targeted therapies became available. The median overall survival in the UTSW cohort was significantly shorter for patients with BAP1-mutant tumours (4·6 years; 95% CI 2·1-7·2), than for patients with PBRM1-mutant tumours (10·6 years; 9·8-11·5), corresponding to a HR of 2·7 (95% CI 0·99-7·6, p=0·044). Median overall survival in the TCGA cohort was 1·9 years (95% CI 0·6-3·3) for patients with BAP1-mutant tumours and 5·4 years (4·0-6·8) for those with PBRM1-mutant tumours. A HR similar to the UTSW cohort was noted in the TCGA cohort (2·8; 95% CI 1·4-5·9; p=0·004). Patients with mutations in both BAP1 and PBRM1, although a minority (three in UTSW cohort and four in TCGA cohort), had the worst overall survival (median 2·1 years, 95% CI 0·3-3·8, for the UTSW cohort, and 0·2 years, 0·0-1·2, for the TCGA cohort). Our findings identify mutation-defined subtypes of clear-cell renal-cell carcinoma with distinct clinical outcomes, a high-risk BAP1-mutant group and a favourable PBRM1-mutant group. These data establish the basis for a molecular genetic classification of clear-cell renal-cell carcinoma that could influence treatment decisions in the future. The existence of different molecular subtypes with disparate outcomes should be considered in the design and assessment of clinical studies. Cancer Prevention and Research Institution of Texas and National Cancer Institute.

Mutation

Kidney Neoplasms - genetics

Reproducibility of Results

Humans

Middle Aged

Carcinoma, Renal Cell - genetics

Male

Transcription Factors - genetics

Kidney Neoplasms - mortality

Ubiquitin Thiolesterase - genetics

Mechanistic Target of Rapamycin Complex 1

Multiprotein Complexes - physiology

Carcinoma, Renal Cell - mortality

Tumor Suppressor Proteins - genetics

Survival Analysis

Female

TOR Serine-Threonine Kinases - physiology

Aged

Retrospective Studies

Nuclear Proteins - genetics

Details

Title: Subtitle: Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation
Creators: Payal Kapur - Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
Samuel Peña-Llopis - Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA
Alana Christie - Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA
Leah Zhrebker - Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
Andrea Pavía-Jiménez - Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA
W Kimryn Rathmell - Departments of Internal Medicine and Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
Xian-Jin Xie - Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA
James Brugarolas - Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA
Resource Type: Journal article
Publication Details: The lancet oncology, Vol.14(2), pp.159-167
Publisher: England
DOI: 10.1016/S1470-2045(12)70584-3
PMID: 23333114
PMCID: PMC4674067
ISSN: 1474-5488
eISSN: 1474-5488
Grant note: 1P30CA142543 / NCI NIH HHS P30 CA142543 / NCI NIH HHS
Language: English
Date published: 02/2013
Academic Unit: Preventive and Community Dentistry; Biostatistics; Dental Research
Record Identifier: 9983917657702771

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