Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
Genes Chromosomes Cancer. 2014 Jan;53(1):38-51. doi: 10.1002/gcc.22116. Epub 2013 Oct 29.
VHL is mutated in the majority of patients with clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent studies have identified recurrent mutations in histone modifying and chromatin remodeling genes, including BAP1, PBRM1, SETD2, KDM6A, and JARID1c. Current evidence suggests that BAP1 mutations are associated with aggressive disease. The clinical significance of the remaining genes is unknown. In this study, targeted sequencing of VHL and JARID1c (entire genes) and coding regions of BAP1, PBRM1, SETD2, and KDM6A was performed on 132 ccRCCs and matched normal tissues. Associations between mutations and clinical and pathological outcomes were interrogated. Inactivation of VHL (coding mutation or promoter methylation) was seen in 75% of ccRCCs. Somatic noncoding VHL alterations were identified in 29% of ccRCCs and may be associated with improved overall survival. BAP1 (11%), PBRM1 (33%), SETD2 (16%), JARID1c (4%), and KDM6A (3%) mutations were identified. BAP1-mutated tumors were associated with metastatic disease at presentation (P = 0.023), advanced clinical stage (P = 0.042) and a trend towards shorter recurrence free survival (P = 0.059) when compared with tumors exclusively mutated for PBRM1. Our results support those of recent publications pointing towards a role for BAP1 and PBRM1 mutations in risk stratifying ccRCCs. Further investigation of noncoding alterations in VHL is warranted.
VHL 在大多数透明细胞肾细胞癌（ccRCC）患者中发生突变，但其临床相关性存在争议。最近的研究已经确定了组蛋白修饰和染色质重塑基因的复发性突变，包括 BAP1、PBRM1、SETD2、KDM6A 和 JARID1c。目前的证据表明，BAP1 突变与侵袭性疾病有关。其余基因的临床意义尚不清楚。在这项研究中，对 132 例 ccRCC 及其匹配的正常组织进行了 VHL 和 JARID1c（整个基因）和 BAP1、PBRM1、SETD2 和 KDM6A 编码区的靶向测序。研究了突变与临床和病理结局之间的关系。在 75%的 ccRCC 中观察到 VHL（编码突变或启动子甲基化）失活。在 29%的 ccRCC 中发现了体细胞非编码 VHL 改变，可能与总生存率的提高有关。鉴定出 BAP1（11%）、PBRM1（33%）、SETD2（16%）、JARID1c（4%）和 KDM6A（3%）突变。与仅发生 PBRM1 突变的肿瘤相比，BAP1 突变的肿瘤在发病时与转移性疾病相关（P=0.023）、临床分期较晚（P=0.042），并且无复发生存时间较短的趋势（P=0.059）。我们的结果支持最近的出版物指出 BAP1 和 PBRM1 突变在 ccRCC 风险分层中的作用。进一步研究 VHL 中的非编码改变是必要的。
