Comprehensive molecular characterization of clear cell renal cell carcinoma.
Comprehensive molecular characterization of clear cell renal cell carcinoma.
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透明细胞肾细胞癌（ccRCC）潜在的遗传变化包括控制细胞氧传感（例如VHL）和染色质状态维持（例如PBRM 1）的基因改变。我们使用不同的基因组平台调查了400多个肿瘤，并确定了19个显著突变的基因。PI 3 K/Akt通路反复突变，表明该通路是潜在的治疗靶点。广泛的DNA低甲基化与H3 K36甲基转移酶SETD 2的突变相关，综合分析表明，涉及SWI/SNF染色质重塑复合物（PBRM 1，ARID 1A，SMARCA 4）的突变可能对其他途径产生深远的影响。侵袭性癌症表现出代谢转变的证据，涉及TCA循环相关基因的下调、AMPK和PTEN蛋白水平的降低、戊糖磷酸途径和谷氨酰胺转运蛋白基因的上调、乙酰辅酶A羧化酶蛋白的增加以及miR-21和GRB 10启动子甲基化的改变。因此，重塑细胞代谢构成了ccRCC的复发模式，与肿瘤分期和严重程度相关，并为疾病治疗提供了新的观点。
Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (e.g. VHL) and the maintenance of chromatin states (e.g. PBRM1). We surveyed more than 400 tumors using different genomic platforms and identified 19 significantly mutated genes. The PI3K/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 remodeling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving down-regulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, up-regulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 and GRB10. Remodeling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumor stage and severity and offers new views on the opportunities for disease treatment.