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

Marco Gerlinger; Stuart Horswell; James Larkin; Andrew J. Rowan; Max P. Salm; Ignacio Varela; Rosalie Fisher; Nicholas Mcgranahan; Nicholas Matthews; Claudio R. Santos; Pierre Martinez; Benjamin Phillimore; Sharmin Begum; Adam Rabinowitz; Bradley Spencer-Dene; Sakshi Gulati; Paul A. Bates; Gordon Stamp; Lisa Pickering; Martin Gore; David L. Nicol; Steven Hazell; P. Andrew Futreal; Aengus Stewart; Charles Swanton

doi:10.1038/ng.2891

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

Marco Gerlinger, Stuart Horswell, James Larkin, Andrew J. Rowan, Max P. Salm, Ignacio Varela, Rosalie Fisher, Nicholas Mcgranahan, Nicholas Matthews, Claudio R. Santos, Pierre Martinez, Benjamin Phillimore, Sharmin Begum, Adam Rabinowitz, Bradley Spencer-Dene, Sakshi Gulati, Paul A. Bates, Gordon Stamp, Lisa Pickering, Martin GoreDavid L. Nicol, Steven Hazell, P. Andrew Futreal, Aengus Stewart, Charles Swanton

Genomic Medicine

Research output: Contribution to journal › Article › peer-review

964 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	225-233
Number of pages	9
Journal	Nature Genetics
Volume	46
Issue number	3
DOIs	https://doi.org/10.1038/ng.2891
State	Published - Mar 2014

ASJC Scopus subject areas

Genetics

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Gerlinger, M., Horswell, S., Larkin, J., Rowan, A. J., Salm, M. P., Varela, I., Fisher, R., Mcgranahan, N., Matthews, N., Santos, C. R., Martinez, P., Phillimore, B., Begum, S., Rabinowitz, A., Spencer-Dene, B., Gulati, S., Bates, P. A., Stamp, G., Pickering, L., ... Swanton, C. (2014). Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nature Genetics, 46(3), 225-233. https://doi.org/10.1038/ng.2891

Gerlinger, M, Horswell, S, Larkin, J, Rowan, AJ, Salm, MP, Varela, I, Fisher, R, Mcgranahan, N, Matthews, N, Santos, CR, Martinez, P, Phillimore, B, Begum, S, Rabinowitz, A, Spencer-Dene, B, Gulati, S, Bates, PA, Stamp, G, Pickering, L, Gore, M, Nicol, DL, Hazell, S, Futreal, PA, Stewart, A & Swanton, C 2014, 'Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing', Nature Genetics, vol. 46, no. 3, pp. 225-233. https://doi.org/10.1038/ng.2891

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title = "Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing",

abstract = "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.",

author = "Marco Gerlinger and Stuart Horswell and James Larkin and Rowan, {Andrew J.} and Salm, {Max P.} and Ignacio Varela and Rosalie Fisher and Nicholas Mcgranahan and Nicholas Matthews and Santos, {Claudio R.} and Pierre Martinez and Benjamin Phillimore and Sharmin Begum and Adam Rabinowitz and Bradley Spencer-Dene and Sakshi Gulati and Bates, {Paul A.} and Gordon Stamp and Lisa Pickering and Martin Gore and Nicol, {David L.} and Steven Hazell and Futreal, {P. Andrew} and Aengus Stewart and Charles Swanton",

note = "Funding Information: We thank the patients, the research nurses at the Royal Marsden Hospital, and Lifetech and Westminster Genomic Services at the University of Westminster, London, for their assistance with validation. C.S. and M. Gerlinger are supported by grants from Cancer Research UK Biomarkers and Imaging Discovery and Development Committee (BIDD), the Medical Research Council and the Seventh European Union Framework Programme, and C.S. is supported by the Breast Cancer Research Foundation and the Rosetrees Trust. We acknowledge the Ram{\'o}n y Cajal program of the Ministerio de Econom{\'i}a y Competitividad, Spain, and Novartis for funding support for E-PREDICT clinical trials. This study was supported by researchers at the National Institute for Health Research Biomedical Research Centres at University College London Hospitals and at the Royal Marsden Hospital.",

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doi = "10.1038/ng.2891",

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AU - Gerlinger, Marco

AU - Horswell, Stuart

AU - Larkin, James

AU - Rowan, Andrew J.

AU - Salm, Max P.

AU - Varela, Ignacio

AU - Fisher, Rosalie

AU - Mcgranahan, Nicholas

AU - Matthews, Nicholas

AU - Santos, Claudio R.

AU - Martinez, Pierre

AU - Phillimore, Benjamin

AU - Begum, Sharmin

AU - Rabinowitz, Adam

AU - Spencer-Dene, Bradley

AU - Gulati, Sakshi

AU - Bates, Paul A.

AU - Stamp, Gordon

AU - Pickering, Lisa

AU - Gore, Martin

AU - Nicol, David L.

AU - Hazell, Steven

AU - Futreal, P. Andrew

AU - Stewart, Aengus

AU - Swanton, Charles

N1 - Funding Information: We thank the patients, the research nurses at the Royal Marsden Hospital, and Lifetech and Westminster Genomic Services at the University of Westminster, London, for their assistance with validation. C.S. and M. Gerlinger are supported by grants from Cancer Research UK Biomarkers and Imaging Discovery and Development Committee (BIDD), the Medical Research Council and the Seventh European Union Framework Programme, and C.S. is supported by the Breast Cancer Research Foundation and the Rosetrees Trust. We acknowledge the Ramón y Cajal program of the Ministerio de Economía y Competitividad, Spain, and Novartis for funding support for E-PREDICT clinical trials. This study was supported by researchers at the National Institute for Health Research Biomedical Research Centres at University College London Hospitals and at the Royal Marsden Hospital.

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N2 - 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.

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

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