Abstract
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.
Key points
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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.
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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).
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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.
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Loss of CDKN2A by deletion of chromosome band 9p21.3 or promoter hypermethylation was frequent in RCC and correlated with poorer survival in all RCC histological subtypes.
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Increased DNA hypermethylation was present in a subset of ccRCC, pRCC and chRCC tumours and correlated with poor survival in all RCC histological subtypes.
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Expression of immune cell gene-specific signatures was increased in ccRCC and CIMP RCC, whereas increased expression of the type 2 T helper cell signature correlated with poorer survival in all RCC histological subtypes.
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The research by the authors discussed in this article was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute and Center for Cancer Research.
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Linehan, W.M., Ricketts, C.J. The Cancer Genome Atlas of renal cell carcinoma: findings and clinical implications. Nat Rev Urol 16, 539–552 (2019). https://doi.org/10.1038/s41585-019-0211-5
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