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Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing

ABSTRACT: We applied multi-region exome sequencing to 10 clear cell renal carcinomas to resolve the genetic architecture, intra tumour heterogeneity and evolutionary histories of these tumours.

PROVIDER: EGAS00001000667 | EGA |

REPOSITORIES: EGA

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Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing.

Gerlinger Marco M Horswell Stuart S Larkin James J Rowan Andrew J AJ Salm Max P MP Varela Ignacio I Fisher Rosalie R McGranahan Nicholas N Matthews Nicholas N Santos Claudio R CR Martinez Pierre P Phillimore Benjamin B Begum Sharmin S Rabinowitz Adam A Spencer-Dene Bradley B Gulati Sakshi S Bates Paul A PA Stamp Gordon G Pickering Lisa L Gore Martin M Nicol David L DL Hazell Steven S Futreal P Andrew PA Stewart Aengus A Swanton Charles C

Nature genetics 20140202 3

Clear cell renal carcinomas (ccRCCs) can display intratumor heterogeneity (ITH). We applied multiregion exome sequencing (M-seq) to resolve the genetic architecture and evolutionary histories of ten ccRCCs. Ultra-deep sequencing identified ITH in all cases. We found that 73-75% of identified ccRCC driver aberrations were subclonal, confounding estimates of driver mutation prevalence. ITH increased with the number of biopsies analyzed, without evidence of saturation in most tumors. Chromosome 3p ...[more]

PMID: 24487277

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Project description:Sarcomatoid transformation, wherein an epithelioid carcinomatous tumour component coexists with a sarcomatoid histology, is a predictor of poor prognosis in clear cell renal cell carcinoma. Our understanding of sarcomatoid change has been hindered by the lack of molecular examination. Thus, we sought to characterize molecularly the biphasic epithelioid and sarcomatoid components of sarcomatoid clear cell renal cell carcinoma and compare them to non-sarcomatoid clear cell renal cell carcinoma. We examined the transcriptome of the epithelioid and sarcomatoid components of advanced stage sarcomatoid clear cell renal cell carcinoma (n=43) and non-sarcomatoid clear cell renal cell carcinoma (n=37) from independent discovery and validation cohorts using the cDNA microarray and RNA-seq platforms. We analyzed DNA copy number profiles, generated using SNP arrays, from patients with sarcomatoid clear cell renal cell carcinoma (n=10) and advanced non-sarcomatoid clear cell renal cell carcinoma (n=155). The epithelioid and sarcomatoid components of sarcomatoid clear cell renal cell carcinoma had similar gene expression and DNA copy number signatures that were, however, distinct from those of high-grade, high-stage non-sarcomatoid clear cell renal cell carcinoma. Prognostic clear cell renal cell carcinoma gene expression profiles were shared by the biphasic components of sarcomatoid clear cell renal cell carcinoma and the sarcomatoid component showed a partial epithelial-to-mesenchymal transition signature. Our genome-scale microarray-based transcript data were validated in an independent set of sarcomatoid and non-sarcomatoid clear cell renal cell carcinomas using RNA-seq. Sarcomatoid clear cell renal cell carcinoma is molecularly distinct from non-sarcomatoid clear cell renal cell carcinoma, with its genetic programming largely shared by its biphasic morphological components. These data explain why a low percentage of sarcomatoid histology augurs a poor prognosis; suggest the need to modify the pathological grading system and introduce the potential for candidate biomarkers to detect sarcomatoid change preoperatively without specifically sampling the histological sarcomatoid component.

Dataset Information

Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing

Publications

Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing.

Similar Datasets

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