Integrated molecular analysis of clear-cell renal cell carcinoma

Abstract

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.

Accumulation of Somatic Mutations in TP53 in Gastric Epithelium With Helicobacter pylori Infection

“…We identified somatic mutations by the strict variant filtering process (Supplementary Figure 1 and Supplementary materials and methods). To validate somatic mutations, we performed PCR-based deep-sequencing using a different deep-sequencing platform (the GS Junior System, Roche) on the non-silent mutations detected by whole exome sequencing, according to the validation protocol reported in the recent study 21 .…”

miR-27b synergizes with anticancer drugs via p53 activation and CYP1B1 suppression

“…In addition, CCNG1 recruits the β-subunit of phosphatase 2A (PP2A) to dephosphorylate MDM2, thereby resulting in p53 degradation [34]. Intriguingly, p53 mutations are rarely identified in human kidney cancers [55]. pVHL, often mutated in kidney cancers, was found to stabilize p53 by suppressing Mdm2-mediated ubiquitination [56].…”

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

“…These biallelic mutations were found in 6 of 19 (31.5%) nonhypermutated tumors. TP53 mutations are otherwise rare in ccRCC (28,35). For example, among 395 ccRCCs reported by TCGA that do not have sarcomatoid elements, only 6 of 395 (1.5%) have TP53 mutation (P = 3 × 10 −6 , Fisher exact test, odds ratio 29), and only two of these mutations are in segments of LOH (Fig.…”