Universal Patterns of Selection in Cancer and Somatic Tissues
Iñigo Martincorena, Keiran M Raine, Moritz Gerstung, Kevin J Dawson, Kerstin Haase, Peter Van Loo, Helen Davies, Michael R Stratton, Peter J Campbell, Iñigo Martincorena, Keiran M Raine, Moritz Gerstung, Kevin J Dawson, Kerstin Haase, Peter Van Loo, Helen Davies, Michael R Stratton, Peter J Campbell
Abstract
Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from molecular evolution and applied them to 7,664 tumors across 29 cancer types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection almost absent outside homozygous loss of essential genes. This allows exome-wide enumeration of all driver coding mutations, including outside known cancer genes. On average, tumors carry ∼4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We systematically catalog cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.
Keywords: cancer; evolution; genomics; mutations; selection.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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- Alexandrov L.B., Nik-Zainal S., Wedge D.C., Aparicio S.A., Behjati S., Biankin A.V., Bignell G.R., Bolli N., Borg A., Børresen-Dale A.L., Australian Pancreatic Cancer Genome Initiative. ICGC Breast Cancer Consortium. ICGC MMML-Seq Consortium. ICGC PedBrain Signatures of mutational processes in human cancer. Nature. 2013;500:415–421.
- Armitage P., Doll R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br. J. Cancer. 1954;8:1–12.
- Auton A., Brooks L.D., Durbin R.M., Garrison E.P., Kang H.M., Korbel J.O., Marchini J.L., McCarthy S., McVean G.A., Abecasis G.R., 1000 Genomes Project Consortium A global reference for human genetic variation. Nature. 2015;526:68–74.
- Beckman R.A., Loeb L.A. Negative clonal selection in tumor evolution. Genetics. 2005;171:2123–2131.
- Blokzijl F., de Ligt J., Jager M., Sasselli V., Roerink S., Sasaki N., Huch M., Boymans S., Kuijk E., Prins P. Tissue-specific mutation accumulation in human adult stem cells during life. Nature. 2016;538:260–264.
- Blomen V.A., Májek P., Jae L.T., Bigenzahn J.W., Nieuwenhuis J., Staring J., Sacco R., van Diemen F.R., Olk N., Stukalov A. Gene essentiality and synthetic lethality in haploid human cells. Science. 2015;350:1092–1096.
- Bolli N., Avet-Loiseau H., Wedge D.C., Van Loo P., Alexandrov L.B., Martincorena I., Dawson K.J., Iorio F., Nik-Zainal S., Bignell G.R. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat. Commun. 2014;5:2997.
- Cairns J. Mutation selection and the natural history of cancer. Nature. 1975;255:197–200.
- Castro-Giner F., Ratcliffe P., Tomlinson I. The mini-driver model of polygenic cancer evolution. Nat. Rev. Cancer. 2015;15:680–685.
- Church D.N., Briggs S.E., Palles C., Domingo E., Kearsey S.J., Grimes J.M., Gorman M., Martin L., Howarth K.M., Hodgson S.V., NSECG Collaborators DNA polymerase ε and δ exonuclease domain mutations in endometrial cancer. Hum. Mol. Genet. 2013;22:2820–2828.
- Dias J., Van Nguyen N., Georgiev P., Gaub A., Brettschneider J., Cusack S., Kadlec J., Akhtar A. Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex. Genes Dev. 2014;28:929–942.
- Forbes S.A., Beare D., Gunasekaran P., Leung K., Bindal N., Boutselakis H., Ding M., Bamford S., Cole C., Ward S. COSMIC: exploring the world’s knowledge of somatic mutations in human cancer. Nucleic Acids Res. 2015;43:D805–D811.
- Fredriksson N.J., Ny L., Nilsson J.A., Larsson E. Systematic analysis of noncoding somatic mutations and gene expression alterations across 14 tumor types. Nat. Genet. 2014;46:1258–1263.
- Galloway A., Saveliev A., Łukasiak S., Hodson D.J., Bolland D., Balmanno K., Ahlfors H., Monzón-Casanova E., Mannurita S.C., Bell L.S. RNA-binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence. Science. 2016;352:453–459.
- Gerstung M., Papaemmanuil E., Campbell P.J. Subclonal variant calling with multiple samples and prior knowledge. Bioinformatics. 2014;30:1198–1204.
- Gerstung M., Papaemmanuil E., Martincorena I., Bullinger L., Gaidzik V.I., Paschka P., Heuser M., Thol F., Bolli N., Ganly P. Precision oncology for acute myeloid leukemia using a knowledge bank approach. Nat. Genet. 2017;49:332–340.
- Goldman N., Yang Z. A codon-based model of nucleotide substitution for protein-coding DNA sequences. Mol. Biol. Evol. 1994;11:725–736.
- Greenman C., Wooster R., Futreal P.A., Stratton M.R., Easton D.F. Statistical analysis of pathogenicity of somatic mutations in cancer. Genetics. 2006;173:2187–2198.
- Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C. Patterns of somatic mutation in human cancer genomes. Nature. 2007;446:153–158.
- Haradhvala N.J., Polak P., Stojanov P., Covington K.R., Shinbrot E., Hess J.M., Rheinbay E., Kim J., Maruvka Y.E., Braunstein L.Z. Mutational strand asymmetries in cancer genomes reveal mechanisms of dna damage and repair. Cell. 2016;164:538–549.
- Hause R.J., Pritchard C.C., Shendure J., Salipante S.J. Classification and characterization of microsatellite instability across 18 cancer types. Nat. Med. 2016;22:1342–1350.
- Jones D., Raine K.M., Davies H., Tarpey P.S., Butler A.P., Teague J.W., Nik-Zainal S., Campbell P.J. cgpCaVEManWrapper: simple execution of CaVEMan in order to detect somatic single nucleotide variants in NGS data. Curr. Protoc. Bioinformatics. 2016;56:15.10.11–15.10.18.
- Kandoth C., McLellan M.D., Vandin F., Ye K., Niu B., Lu C., Xie M., Zhang Q., McMichael J.F., Wyczalkowski M.A. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–339.
- Kryazhimskiy S., Plotkin J.B. The population genetics of dN/dS. PLoS Genet. 2008;4:e1000304.
- Kundaje A., Meuleman W., Ernst J., Bilenky M., Yen A., Heravi-Moussavi A., Kheradpour P., Zhang Z., Wang J., Ziller M.J., Roadmap Epigenomics Consortium Integrative analysis of 111 reference human epigenomes. Nature. 2015;518:317–330.
- Lawrence M.S., Stojanov P., Polak P., Kryukov G.V., Cibulskis K., Sivachenko A., Carter S.L., Stewart C., Mermel C.H., Roberts S.A. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499:214–218.
- Lawrence M.S., Stojanov P., Mermel C.H., Robinson J.T., Garraway L.A., Golub T.R., Meyerson M., Gabriel S.B., Lander E.S., Getz G. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014;505:495–501.
- Lee W., Jiang Z., Liu J., Haverty P.M., Guan Y., Stinson J., Yue P., Zhang Y., Pant K.P., Bhatt D. The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature. 2010;465:473–477.
- Lee H., Palm J., Grimes S.M., Ji H.P. The Cancer Genome Atlas Clinical Explorer: a web and mobile interface for identifying clinical-genomic driver associations. Genome Med. 2015;7:112.
- Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T., O’Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., Exome Aggregation Consortium Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–291.
- Martincorena I., Campbell P.J. Somatic mutation in cancer and normal cells. Science. 2015;349:1483–1489.
- Martincorena I., Seshasayee A.S., Luscombe N.M. Evidence of non-random mutation rates suggests an evolutionary risk management strategy. Nature. 2012;485:95–98.
- Martincorena I., Roshan A., Gerstung M., Ellis P., Van Loo P., McLaren S., Wedge D.C., Fullam A., Alexandrov L.B., Tubio J.M. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science. 2015;348:880–886.
- McFarland C.D., Korolev K.S., Kryukov G.V., Sunyaev S.R., Mirny L.A. Impact of deleterious passenger mutations on cancer progression. Proc. Natl. Acad. Sci. USA. 2013;110:2910–2915.
- McFarland C.D., Mirny L.A., Korolev K.S. Tug-of-war between driver and passenger mutations in cancer and other adaptive processes. Proc. Natl. Acad. Sci. USA. 2014;111:15138–15143.
- McGranahan N., Furness A.J., Rosenthal R., Ramskov S., Lyngaa R., Saini S.K., Jamal-Hanjani M., Wilson G.A., Birkbak N.J., Hiley C.T. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351:1463–1469.
- Miyata T., Yasunaga T. Molecular evolution of mRNA: a method for estimating evolutionary rates of synonymous and amino acid substitutions from homologous nucleotide sequences and its application. J. Mol. Evol. 1980;16:23–36.
- Morley A.A. The somatic mutation theory of ageing. Mutat. Res. 1995;338:19–23.
- Mularoni L., Sabarinathan R., Deu-Pons J., Gonzalez-Perez A., López-Bigas N. OncodriveFML: a general framework to identify coding and non-coding regions with cancer driver mutations. Genome Biol. 2016;17:128.
- Nei M., Gojobori T. Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol. Biol. Evol. 1986;3:418–426.
- Nielsen R., Yang Z. Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene. Genetics. 1998;148:929–936.
- Nik-Zainal S., Davies H., Staaf J., Ramakrishna M., Glodzik D., Zou X., Martincorena I., Alexandrov L.B., Martin S., Wedge D.C. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 2016;534:47–54.
- Nordling C.O. A new theory on cancer-inducing mechanism. Br. J. Cancer. 1953;7:68–72.
- Nowell P.C. The clonal evolution of tumor cell populations. Science. 1976;194:23–28.
- Ostrow S.L., Barshir R., DeGregori J., Yeger-Lotem E., Hershberg R. Cancer evolution is associated with pervasive positive selection on globally expressed genes. PLoS Genet. 2014;10:e1004239.
- Pleasance E.D., Cheetham R.K., Stephens P.J., McBride D.J., Humphray S.J., Greenman C.D., Varela I., Lin M.L., Ordóñez G.R., Bignell G.R. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. 2010;463:191–196.
- Pleasance E.D., Stephens P.J., O’Meara S., McBride D.J., Meynert A., Jones D., Lin M.L., Beare D., Lau K.W., Greenman C. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature. 2010;463:184–190.
- Polak P., Karlić R., Koren A., Thurman R., Sandstrom R., Lawrence M., Reynolds A., Rynes E., Vlahoviček K., Stamatoyannopoulos J.A., Sunyaev S.R. Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature. 2015;518:360–364.
- Raine K.M., Hinton J., Butler A.P., Teague J.W., Davies H., Tarpey P., Nik-Zainal S., Campbell P.J. cgpPindel: identifying somatically acquired insertion and deletion events from paired end sequencing. Curr. Protoc. Bioinformatics. 2015;52:15.17.11–15.17.12.
- Raine K.M., Van Loo P., Wedge D.C., Jones D., Menzies A., Butler A.P., Teague J.W., Tarpey P., Nik-Zainal S., Campbell P.J. ascatNgs: Identifying somatically acquired copy-number alterations from whole-genome sequencing data. Curr Protoc Bioinformatics. 2016;56:15.9.1–15.9.17.
- Rajasagi M., Shukla S.A., Fritsch E.F., Keskin D.B., DeLuca D., Carmona E., Zhang W., Sougnez C., Cibulskis K., Sidney J. Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood. 2014;124:453–462.
- Rayner E., van Gool I.C., Palles C., Kearsey S.E., Bosse T., Tomlinson I., Church D.N. A panoply of errors: polymerase proofreading domain mutations in cancer. Nat. Rev. Cancer. 2016;16:71–81.
- Rooney M.S., Shukla S.A., Wu C.J., Getz G., Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160:48–61.
- Rubio-Perez C., Tamborero D., Schroeder M.P., Antolín A.A., Deu-Pons J., Perez-Llamas C., Mestres J., Gonzalez-Perez A., Lopez-Bigas N. In silico prescription of anticancer drugs to cohorts of 28 tumor types reveals targeting opportunities. Cancer Cell. 2015;27:382–396.
- Schuster-Böckler B., Lehner B. Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature. 2012;488:504–507.
- Sherry S.T., Ward M.H., Kholodov M., Baker J., Phan L., Smigielski E.M., Sirotkin K. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29:308–311.
- Shlien A., Campbell B.B., de Borja R., Alexandrov L.B., Merico D., Wedge D., Van Loo P., Tarpey P.S., Coupland P., Behjati S., Biallelic Mismatch Repair Deficiency Consortium Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nat. Genet. 2015;47:257–262.
- Strønen E., Toebes M., Kelderman S., van Buuren M.M., Yang W., van Rooij N., Donia M., Böschen M.L., Lund-Johansen F., Olweus J., Schumacher T.N. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science. 2016;352:1337–1341.
- Supek F., Miñana B., Valcárcel J., Gabaldón T., Lehner B. Synonymous mutations frequently act as driver mutations in human cancers. Cell. 2014;156:1324–1335.
- Tomasetti C., Marchionni L., Nowak M.A., Parmigiani G., Vogelstein B. Only three driver gene mutations are required for the development of lung and colorectal cancers. Proc. Natl. Acad. Sci. USA. 2015;112:118–123.
- Van den Eynden J., Basu S., Larsson E. Somatic mutation patterns in hemizygous genomic regions unveil purifying selection during tumor evolution. PLoS Genet. 2016;12:e1006506.
- Van Loo P., Nordgard S.H., Lingjærde O.C., Russnes H.G., Rye I.H., Sun W., Weigman V.J., Marynen P., Zetterberg A., Naume B. Allele-specific copy number analysis of tumors. Proc. Natl. Acad. Sci. USA. 2010;107:16910–16915.
- Vogelstein B., Papadopoulos N., Velculescu V.E., Zhou S., Diaz L.A., Jr., Kinzler K.W. Cancer genome landscapes. Science. 2013;339:1546–1558.
- Wang K., Li M., Hadley D., Liu R., Glessner J., Grant S.F., Hakonarson H., Bucan M. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res. 2007;17:1665–1674.
- Welch J.S., Ley T.J., Link D.C., Miller C.A., Larson D.E., Koboldt D.C., Wartman L.D., Lamprecht T.L., Liu F., Xia J. The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012;150:264–278.
- Wong C.C., Martincorena I., Rust A.G., Rashid M., Alifrangis C., Alexandrov L.B., Tiffen J.C., Kober C., Green A.R., Massie C.E., Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium Inactivating CUX1 mutations promote tumorigenesis. Nat. Genet. 2014;46:33–38.
- Xie M., Lu C., Wang J., McLellan M.D., Johnson K.J., Wendl M.C., McMichael J.F., Schmidt H.K., Yellapantula V., Miller C.A. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 2014;20:1472–1478.
- Yang Z. PAML 4: phylogenetic analysis by maximum likelihood. Mol. Biol. Evol. 2007;24:1586–1591.
- Yang Z., Bielawski J.P. Statistical methods for detecting molecular adaptation. Trends Ecol. Evol. 2000;15:496–503.
- Yang Z., Nielsen R. Estimating synonymous and nonsynonymous substitution rates under realistic evolutionary models. Mol. Biol. Evol. 2000;17:32–43.
- Yang Z., Ro S., Rannala B. Likelihood models of somatic mutation and codon substitution in cancer genes. Genetics. 2003;165:695–705.
- Yates L.R., Gerstung M., Knappskog S., Desmedt C., Gundem G., Van Loo P., Aas T., Alexandrov L.B., Larsimont D., Davies H. Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nat. Med. 2015;21:751–759.
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