Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Nat Genet. 2013 Aug;45(8):860-7. doi: 10.1038/ng.2699. Epub 2013 Jun 24.
Clear-cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer and its molecular pathogenesis is incompletely understood. Here we report an integrated molecular study of ccRCC in which ≥100 ccRCC cases were fully analyzed by whole-genome and/or whole-exome and RNA sequencing as well as by array-based gene expression, copy number and/or methylation analyses. We identified a full spectrum of genetic lesions and analyzed gene expression and DNA methylation signatures and determined their impact on tumor behavior. Defective VHL-mediated proteolysis was a common feature of ccRCC, which was caused not only by VHL inactivation but also by new hotspot TCEB1 mutations, which abolished Elongin C-VHL binding, leading to HIF accumulation. Other newly identified pathways and components recurrently mutated in ccRCC included PI3K-AKT-mTOR signaling, the KEAP1-NRF2-CUL3 apparatus, DNA methylation, p53-related pathways and mRNA processing. This integrated molecular analysis unmasked new correlations between DNA methylation, gene mutation and/or gene expression and copy number profiles, enabling the stratification of clinical risks for patients with ccRCC.
透明细胞肾细胞癌（ccRCC）是最常见的肾癌，其分子发病机制尚不完全清楚。在这里，我们报告了对 ccRCC 的综合分子研究，其中≥100 例 ccRCC 病例通过全基因组和/或全外显子和 RNA 测序以及基于阵列的基因表达、拷贝数和/或甲基化分析进行了全面分析。我们鉴定了一系列全面的遗传病变，并分析了基因表达和 DNA 甲基化特征，并确定了它们对肿瘤行为的影响。VHL 介导的蛋白水解缺陷是 ccRCC 的一个共同特征，这不仅是由 VHL 失活引起的，还与新的热点 TCEB1 突变有关，这些突变消除了 Elongin C-VHL 结合，导致 HIF 积累。在 ccRCC 中反复突变的其他新鉴定的途径和成分包括 PI3K-AKT-mTOR 信号通路、KEAP1-NRF2-CUL3 装置、DNA 甲基化、p53 相关途径和 mRNA 处理。这种综合的分子分析揭示了 DNA 甲基化、基因突变和/或基因表达与拷贝数谱之间的新相关性，使 ccRCC 患者的临床风险分层成为可能。
