The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes including BAP1. BAP1, a nuclear deubiquitinase, is inactivated in 15% of clear-cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation, but not H2AK119ub1 deubiquitination. BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Interestingly, BAP1 and PBRM1 mutations anticorrelate in tumors (P=3×10−5), and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q=0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q=0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.
SUMMARY Background Clear cell renal cell carcinoma (ccRCC) displays a variety of clinical behaviors. However, the molecular genetic events driving these behaviors are unknown. We discovered that BAP1 is mutated in approximately 15% of ccRCC 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 tumors 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 tumors and those with tumors 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 localized 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 tumors (4.6 years; 95% CI 2.1-7.2), than for patients with PBRM1-mutant tumors (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 tumors and 5.4 years (4.0-6.8) for those with PBRM1-mutant tumors. 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 ccRCC with distinct clinical outcomes, a high-risk BAP1-mutant group and a favorable PBRM1-mutant group. These data establish the basis for a molecular genetic classification of ccRCC that could influence treatment decisions in the future. The existence of different molecular subtypes with disparate outcomes should be considered in the design and evaluation of clinical studies. Funding Cancer Prevention and Research Institution of Texas and NCI.
BackgroundPrimary cardiac angiosarcomas are rare, but they are the most aggressive type of primary cardiac neoplasms. When patients do present, it is with advanced pulmonary and/or cardiac symptoms. Therefore, many times the correct diagnosis is not made at the time of initial presentation. These patients have metastatic disease and the vast majority of these patients die within a few months after diagnosis. Currently the treatment choices are limited and there are no targeted therapies available.Case presentationA 56-year-old male presented with shortness of breath, night sweats, and productive cough for a month. Workup revealed pericardial effusion and multiple bilateral pulmonary nodules suspicious for metastatic disease. Transthoracic echocardiogram showed a large pericardial effusion and a large mass in the base of the right atrium. Results of biopsy of bilateral lung nodules established a diagnosis of primary cardiac angiosarcoma. Aggressive pulmonary disease caused rapid deterioration; the patient went on hospice and subsequently died. Whole exome sequencing of the patient’s postmortem tumor revealed a novel KDR (G681R) mutation, and focal high-level amplification at chromosome 1q encompassing MDM4, a negative regulator of TP53.ConclusionMutations in KDR have been reported previously in angiosarcomas. Previous studies also demonstrated that KDR mutants with constitutive KDR activation could be inhibited with specific KDR inhibitors in vitro. Thus, patients harboring activating KDR mutations could be candidates for treatment with KDR-specific inhibitors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-3000-z) contains supplementary material, which is available to authorized users.
volume 44 | number 9 | SePTember 2012 | nature genetics e r r ata a n d c o r r i g e n d a In the version of this article initially published, there were errors in the consortium membership list and the associated affiliations and in the acknowledgements and contributions sections. These errors and their corrections are detailed below by section.Consortium members: Janice M. Fullerton was omitted from the membership list and has now been added with affiliations 76 and 77. Phil H.
Systemic mastocytosis (SM) is a condition associated with a clonal neoplastic proliferation of mast cells. Approximately 40% of patients with SM present with an associated clonal hematological non-mast cell lineage disorder. Patients presenting with SM-acute myeloid leukemia (AML) have the worst prognosis. We present a case of a 62-year-old woman who was diagnosed with SM-AML. After initial treatment with a standard regimen of cytosine arabinoside (Ara-C)/idarubicin, her bone marrow showed residual blasts. She was subsequently treated with a second induction regimen of clofarabine and high-dose Ara-C, which resulted in remission of AML, although a residual mast cell infiltrate persisted in her bone marrow. After consolidation therapy with clofarabine/Ara-C, the patient received a stem cell allograft. A follow-up bone marrow showed no residual blasts but persistent mast cells occupying about 5% of the marrow volume.
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