Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation.
Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation.
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DOI：
10.1016/s1470-2045(12)70584-3
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发表时间：
2013-02
期刊：
影响因子：
--
通讯作者：
Brugarolas J
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文献类型：
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作者：
Kapur P;Peña-Llopis S;Christie A;Zhrebker L;Pavía-Jiménez A;Rathmell WK;Xie XJ;Brugarolas J
肾透明细胞癌（ccRCC）具有多种临床表现。然而，驱动这些行为的分子遗传事件是未知的。我们发现，BAP 1在大约15%的ccRCC中发生突变，并且BAP 1和PBRM 1突变在很大程度上是相互排斥的。本研究的目的是研究这些分子亚型的临床病理学意义，并确定BAP 1突变型和PBRM 1突变型肿瘤患者的总生存率是否不同。在这项回顾性分析中，我们评估了1998年至2011年间来自美国德克萨斯州德克萨斯大学西南医学中心（UTSW）的145例原发性透明细胞肾细胞癌患者，并确定了PBRM 1和BAP 1突变状态。我们将患者分为BAP 1突变型肿瘤患者和PBRM 1突变型肿瘤患者。我们使用来自癌症基因组图谱（TCGA）的第二个独立队列（n=327）进行验证。在这两个队列中，超过80%的患者在就诊时患有局部或局部疾病。总体而言，两个队列相似，尽管TCGA有更多的转移性和高级别疾病患者，并且在分子靶向治疗可用之前有更多的TCGA患者。UTSW队列中BAP 1突变型肿瘤患者的中位总生存期（4.6年; 95% CI 2.1-7.2）显著短于PBRM 1突变型肿瘤患者（10.6年; 9.8-11.5），对应的HR为2.7（95% CI 0.99-7.6，p=0.044）。在TCGA队列中，BAP 1突变型肿瘤患者的中位总生存期为1.9年（95% CI 0.6-3.3），PBRM 1突变型肿瘤患者为5.4年（4.0-6.8）。在TCGA队列中观察到与UTSW队列相似的HR（2.8; 95% CI 1.4-5.9; p=0.004）。BAP 1和PBRM 1均存在突变的患者虽然是少数（UTSW队列中3例，TCGA队列中4例），但总生存期最差（UTSW队列中位生存期为2.1年，95% CI 0.3-3.8; TCGA队列中位生存期为0.2年，95% CI 0.0-1.2）。我们的研究结果确定了具有不同临床结局的突变定义的ccRCC亚型，高风险BAP 1突变组和有利的PBRM 1突变组。这些数据为ccRCC的分子遗传学分类奠定了基础，这可能会影响未来的治疗决策。在临床研究的设计和评价中，应考虑不同分子亚型的存在和不同的结局。得克萨斯州癌症预防和研究所和NCI。
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. 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. 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). 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. Cancer Prevention and Research Institution of Texas and NCI.