The Cancer Genome Atlas of renal cell carcinoma: findings and clinical implications

• Published in: Nature reviews. Urology 2019-09, Vol.16 (9), p.539-552
• Main Authors: Linehan, W. Marston, Ricketts, Christopher J.
• Format: Article
• Language: English
• Subjects: 692/308/575; 692/699/67/1059; 692/699/67/589/1588/1351; 692/699/67/69; Carcinoma, Renal cell; Carcinoma, Renal Cell - classification; Carcinoma, Renal Cell - diagnosis; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - therapy; Care and treatment; Development and progression; Epigenetics; Epigenomics; Gene expression; Gene mutations; Genetic aspects; Genome; Genomes; Genotype; Health aspects; Humans; Identification and classification; Kidney cancer; Kidney Neoplasms - classification; Kidney Neoplasms - diagnosis; Kidney Neoplasms - genetics; Kidney Neoplasms - therapy; Medicine; Medicine & Public Health; Metabolism; Mutation; Review Article; Urology
• ISSN: 1759-4812; 1759-4820
• DOI: 10.1038/s41585-019-0211-5

The Cancer Genome Atlas (TCGA) characterized the somatic genetic and genomic alterations in renal cell carcinoma (RCC) encompassing the major RCC histological subtypes, including clear cell RCC (ccRCC), papillary RCC (pRCC) and chromophobe RCC (chRCC). Unique distinguishing features were found between the RCC subtypes, including in chromosomal alterations and tumour metabolism, as well as within each RCC subtype, of which some correlated with differences in patient survival. Two new RCC subtypes were defined by distinct epigenetic and metabolic pathway expression patterns, the hypermethylated CpG island methylator phenotype-associated (CIMP) RCCs and metabolically divergent chRCCs, and new biomarkers of poor patient outcome were identified, including PBRM1 mutation in type 1 pRCC and CDKN2A loss in chRCC. Expression of many immune cell gene-specific signatures was increased in ccRCC compared with pRCC and chRCC, and expression of select signatures, including the type 2 T helper cell signature, was increased in CIMP RCC. Increased expression of the type 2 T helper cell signature correlated with poorer survival in ccRCC, pRCC and chRCC. In addition to improving our current understanding of RCC, TCGA RCC studies are an invaluable resource that provides the foundation for the development of improved methods for diagnosis, treatment and prevention of this disease. This Review by Ricketts and Linehan comprehensively summarizes the findings of The Cancer Genome Atlas analyses of renal cell carcinoma and their clinical implications. The authors highlight unique and shared features of the tumour histological subtypes, their predictive power and their possible utility as therapeutic targets. Key points The Cancer Genome Atlas (TCGA) analyses of renal cell carcinoma (RCC) highlight the fundamental differences between the major histological RCC subtypes, such as their distinct chromosomal alterations and metabolic pathway expression signatures. Two novel RCC subtypes were identified by distinct epigenetic and mRNA expression features, the hypermethylated CpG island methylator phenotype-associated (CIMP) RCCs and the metabolically divergent chromophobe RCCs (chRCCs). Mutation of chromatin-remodelling genes was common in clear cell RCC (ccRCC) and present in some papillary RCCs (pRCCs) with BAP1 and PBRM1 mutations, correlating with poor survival in ccRCC and pRCC, respectively. Loss of CDKN2A by deletion of chromosome band 9p21.3 or promoter hypermethylation was freque