Journal
NATURE GENETICS
Volume 46, Issue 3, Pages 225-+Publisher
NATURE RESEARCH
DOI: 10.1038/ng.2891
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Funding
- Cancer Research UK Biomarkers and Imaging Discovery and Development Committee (BIDD)
- Medical Research Council
- Seventh European Union Framework Programme
- Breast Cancer Research Foundation
- Rosetrees Trust
- Ramon y Cajal program of the Ministerio de Economia y Competitividad, Spain
- Novartis
- National Institute for Health Research Biomedical Research Centres at University College London Hospitals
- Royal Marsden Hospital
- MRC [G0902275] Funding Source: UKRI
- Cancer Research UK [10748] Funding Source: researchfish
- Medical Research Council [G0902275] Funding Source: researchfish
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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 loss and VHL aberrations were the only ubiquitous events. The proportion of C>T transitions at CpG sites increased during tumor progression. M-seq permits the temporal resolution of ccRCC evolution and refines mutational signatures occurring during tumor development.
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