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 Pavia-Jimenez,W. Kimryn Rathmell,Xian Jin Xie,James Brugarolas +7 more
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TLDR
The findings establish the basis for a molecular genetic classification of clear-cell renal-cell carcinoma with distinct clinical outcomes, a high-risk BAP1-mutant group and a favourable PBRM1-Mutant group.Abstract:
Summary Background 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. Methods 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. Findings 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). Interpretation 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. Funding Cancer Prevention and Research Institution of Texas and National Cancer Institute.read more
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References
More filters
Journal ArticleDOI
Controlling the false discovery rate: a practical and powerful approach to multiple testing
Yoav Benjamini,Yosef Hochberg +1 more
TL;DR: In this paper, a different approach to problems of multiple significance testing is presented, which calls for controlling the expected proportion of falsely rejected hypotheses -the false discovery rate, which is equivalent to the FWER when all hypotheses are true but is smaller otherwise.
Book
AJCC Cancer Staging Manual
Mahul B. Amin,Stephen B. Edge,Frederick L. Greene,David R. Byrd,Robert K. Brookland,Mary Kay Washington,Jeffrey E. Gershenwald,Carolyn C. Compton,Kenneth R. Hess,Daniel C. Sullivan,J. Milburn Jessup,James D. Brierley,Lauri E. Gaspar,Richard L. Schilsky,Charles M. Balch,David P. Winchester,Elliot A. Asare,Martin Madera,Donna M. Gress,Laura R. Meyer +19 more
TL;DR: Purposes and Principles of Cancer Staging and End-Results Reporting are explained.
Journal ArticleDOI
Cancer statistics, 2012
TL;DR: The reduction in overall cancer death rates since 1990 in men and 1991 in women translates to the avoidance of about 1,024,400 deaths from cancer, which can be accelerated by applying existing cancer control knowledge across all segments of the population, with an emphasis on those groups in the lowest socioeconomic bracket.
Journal ArticleDOI
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.
Marco Gerlinger,Andrew Rowan,Stuart Horswell,James Larkin,David Endesfelder,Eva Grönroos,Pierre Martinez,Nicholas Matthews,Aengus Stewart,Patrick S. Tarpey,Ignacio Varela,Benjamin Phillimore,Sharmin Begum,Neil Q. McDonald,Adam Butler,David T. Jones,Keiran Raine,Calli Latimer,Claudio R. Santos,Mahrokh Nohadani,Aron Charles Eklund,Bradley Spencer-Dene,Graham Clark,Lisa Pickering,Gordon Stamp,Martin Gore,Zoltan Szallasi,Zoltan Szallasi,Julian Downward,P. Andrew Futreal,Charles Swanton +30 more
TL;DR: Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development.
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