Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing
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Article
Nature Genetics volume 46, pages 225–233 (2014) | Download Citation
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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Kern, S.E. Why your new cancer biomarker may never work: recurrent patterns and remarkable diversity in biomarker failures. Cancer Res. 72, 6097–6101 (2012).
Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).
Anderson, K. et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469, 356–361 (2011).
Sottoriva, A. et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc. Natl. Acad. Sci. USA 110, 4009–4014 (2013).
Thirlwell, C. et al. Clonality assessment and clonal ordering of individual neoplastic crypts shows polyclonality of colorectal adenomas. Gastroenterology 138, 1441–1454 (2010).
Campbell, P.J. et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467, 1109–1113 (2010).
Bashashati, A. et al. Distinct evolutionary trajectories of primary high-grade serous ovarian cancers revealed through spatial mutational profiling. J. Pathol. 231, 21–34 (2013).
Navin, N. et al. Tumour evolution inferred by single-cell sequencing. Nature 472, 90–94 (2011).
Gerlinger, M. & Swanton, C. How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine. Br. J. Cancer 103, 1139–1143 (2010).
Yap, T.A., Gerlinger, M., Futreal, P.A., Pusztai, L. & Swanton, C. Intratumor heterogeneity: seeing the wood for the trees. Sci. Transl. Med. 4, 127ps10 (2012).
Nickerson, M.L. et al. Improved identification of von Hippel–Lindau gene alterations in clear cell renal tumors. Clin. Cancer Res. 14, 4726–4734 (2008).
Herman, J.G. et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc. Natl. Acad. Sci. USA 91, 9700–9704 (1994).
Rothberg, J.M. et al. An integrated semiconductor device enabling non-optical genome sequencing. Nature 475, 348–352 (2011).
Houghton, P.J. Everolimus. Clin. Cancer Res. 16, 1368–1372 (2010).
Sato, Y. et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat. Genet. 45, 860–867 (2013).
Nik-Zainal, S. et al. The life history of 21 breast cancers. Cell 149, 994–1007 (2012).
Shah, S.P. et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486, 395–399 (2012).
Dalgliesh, G.L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).
Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).
Guo, G. et al. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat. Genet. 44, 17–19 (2012).
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).
Forbes, S.A. et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 39, D945–D950 (2011).
Kapur, P. et al. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol. 14, 159–167 (2013).
Peña-Llopis, S. et al. BAP1 loss defines a new class of renal cell carcinoma. Nat. Genet. 44, 751–759 (2012).
Foster, K. et al. Somatic mutations of the von Hippel–Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum. Mol. Genet. 3, 2169–2173 (1994).
Kang, S., Bader, A.G. & Vogt, P.K. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc. Natl. Acad. Sci. USA 102, 802–807 (2005).
Martinez, P. et al. Parallel evolution of tumor subclones mimics diversity between tumors. J. Pathol. 230, 356–364 (2013).
Beroukhim, R. et al. Patterns of gene expression and copy-number alterations in von-Hippel Lindau disease–associated and sporadic clear cell carcinoma of the kidney. Cancer Res. 69, 4674–4681 (2009).
Alexandrov, L.B., Nik-Zainal, S., Wedge, D.C., Campbell, P.J. & Stratton, M.R. Deciphering signatures of mutational processes operative in human cancer. Cell Rep. 3, 246–259 (2013).
La Rochelle, J. et al. Chromosome 9p deletions identify an aggressive phenotype of clear cell renal cell carcinoma. Cancer 116, 4696–4702 (2010).
Swanton, C. Intratumor heterogeneity: evolution through space and time. Cancer Res. 72, 4875–4882 (2012).
Turcotte, S. et al. A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Cancer Cell 14, 90–102 (2008).
Bommi-Reddy, A. et al. Kinase requirements in human cells: III. altered kinase requirements in VHL−/− cancer cells detected in a pilot synthetic lethal screen. Proc. Natl. Acad. Sci. USA 105, 16484–16489 (2008).
Chan, D.A. et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci. Transl. Med. 3, 94ra70 (2011).
Rubin, A.F. & Green, P. Mutation patterns in cancer genomes. Proc. Natl. Acad. Sci. USA 106, 21766–21770 (2009).
Hodgkinson, A. & Eyre-Walker, A. Variation in the mutation rate across mammalian genomes. Nat. Rev. Genet. 12, 756–766 (2011).
Ye, K., Schulz, M.H., Long, Q., Apweiler, R. & Ning, Z. Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads. Bioinformatics 25, 2865–2871 (2009).
Robinson, J.T. et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 (2011).
Nakamura, K. et al. Sequence-specific error profile of Illumina sequencers. Nucleic Acids Res. 39, e90 (2011).
Purdom, P.W. Jr., Bradford, P.G., Tamura, K. & Kumar, S. Single column discrepancy and dynamic max-mini optimizations for quickly finding the most parsimonious evolutionary trees. Bioinformatics 16, 140–151 (2000).
Tamura, K. et al. MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol. Biol. Evol. 28, 2731–2739 (2011).
Koboldt, D.C. et al. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res. 22, 568–576 (2012).
Nilsen, G. et al. Copy number: efficient algorithms for single- and multi-track copy number segmentation. BMC Genomics 13, 591 (2012).
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.
These authors contributed equally to this work.
M. Gerlinger, J.L. and C.S. designed the study. R.F., L.P., M. Gore, D.L.N. and J.L. provided clinical specimens. M. Gerlinger, A.J.R. and R.F. processed the samples. G.S., B.S.-D. and S. Hazell performed histopathological analyses. N. Matthews, B.P., S.B., A.J.R. and A.R. sequenced the samples. S. Horswell, I.V., N. McGranahan, M.P.S., P.M., S.G., P.A.B., A.S. and M. Gerlinger performed bioinformatics analyses. B.S.-D. processed histological samples, which were analyzed by G.S. and S. Horswell. M. Gerlinger, N. McGranahan and C.R.S. analyzed all data. M. Gerlinger, N. McGranahan, C.R.S., P.A.F., J.L. and C.S. interpreted the data. M. Gerlinger, N. McGranahan, C.R.S. and C.S. wrote the manuscript. All authors read and approved the final manuscript.
The authors declare no competing financial interests.
Correspondence to Charles Swanton.
Supplementary Tables 1, 2, 4 and 7, Supplementary Figures 1–10 and Supplementary Note
Details of nonsynonymous somatic mutations by region
Variant allele frequencies by region
Nonsynonymous somatic mutations by inferred subclone
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13 September 2013
13 January 2014
02 February 2014
https://doi.org/10.1038/ng.2891
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Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing
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