Nature. 2013 Jul 4;499(7456):43-9. doi: 10.1038/nature12222. Epub 2013 Jun 23.
Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3)K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment.
导致肾透明细胞癌（ccRCC）的遗传变化包括控制细胞氧感应的基因（例如 VHL）和染色质状态维持的基因（例如 PBRM1）的改变。我们使用不同的基因组平台对 400 多个肿瘤进行了调查，发现了 19 个明显突变的基因。PI(3)K/AKT 通路经常发生突变，表明该通路可能是一个潜在的治疗靶点。广泛的 DNA 低甲基化与 H3K36 甲基转移酶 SETD2 的突变有关，综合分析表明，涉及 SWI/SNF 染色质重塑复合物（PBRM1、ARID1A、SMARCA4）的突变可能对其他途径产生深远影响。侵袭性癌症表现出代谢转变的证据，涉及 TCA 循环相关基因下调、AMPK 和 PTEN 蛋白水平降低、戊糖磷酸途径和谷氨酰胺转运基因上调、乙酰辅酶 A 羧化酶蛋白增加，以及 miR-21（也称为 MIR21）和 GRB10 的启动子甲基化改变。因此，重塑细胞代谢在 ccRCC 中是一种反复出现的模式，与肿瘤分期和严重程度相关，并为疾病治疗提供了新的视角。
