Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation
Menée sur une cohorte de 145 patients atteints d'un carcinome rénal sporadique à cellules claires et validée sur une cohorte indépendante incluant 327 patients, cette étude rétrospective américaine identifie les caractéristiques clinicopathologiques de la maladie associées à des mutations des gènes BAP1 et PBRM1 et analyse les effets de ces mutations sur la survie globale des patients
Clear-cell renal-cell carcinomas display divergent clinical behaviours. However, the molecular genetic events driving these behaviours are unknown. We discovered thatBAP1is mutated in about 15% of clear-cell renal-cell carcinoma, and thatBAP1andPBRM1mutations are largely mutually exclusive. The aim of this study was to investigate the clinicopathological significance of these molecular subtypes and to determine whether patients withBAP1-mutant andPBRM1-mutant tumours had different overall survival. In this retrospective analysis, we assessed 145 patients with primary clear-cell renal-cell carcinoma and definedPBRM1andBAP1mutation status from the University of Texas Southwestern Medical Center (UTSW), TX, USA, between 1998 and 2011. We classified patients into those withBAP1-mutant tumours and those with tumours exclusively mutated forPBRM1(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 withBAP1-mutant tumours (4·6 years; 95% CI 2·1?7·2), than for patients withPBRM1-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 withBAP1-mutant tumours and 5·4 years (4·0?6·8) for those withPBRM1-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 bothBAP1andPBRM1, 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-riskBAP1-mutant group and a favourablePBRM1-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.
The Lancet Oncology , résumé, 2012