Comprehensive molecular characterization of clear cell renal cell carcinoma

TLDR

Genetic alterations in clear cell renal cell carcinoma involve disruptions in oxygen‑sensing genes such as VHL and chromatin‑regulating genes like PBRM1. The authors surveyed over 400 tumors with multiple genomic platforms and identified 19 significantly mutated genes. They reported recurrent PI3K/AKT pathway mutations, SETD2‑associated DNA hypomethylation, frequent SWI/SNF complex alterations, and a metabolic reprogramming signature—downregulation of TCA cycle genes, reduced AMPK/PTEN, upregulation of the pentose phosphate and glutamine transport pathways, increased acetyl‑CoA carboxylase, and altered miR‑21/GRB10 methylation—that correlates with tumor stage and severity, suggesting new therapeutic opportunities.

Abstract

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.