Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Feb 18;463(7283):893-8.
doi: 10.1038/nature08768.

Signatures of mutation and selection in the cancer genome

Graham R Bignell  1 , Chris D Greenman, Helen Davies, Adam P Butler, Sarah Edkins, Jenny M Andrews, Gemma Buck, Lina Chen, David Beare, Calli Latimer, Sara Widaa, Jonathon Hinton, Ciara Fahey, Beiyuan Fu, Sajani Swamy, Gillian L Dalgliesh, Bin T Teh, Panos Deloukas, Fengtang Yang, Peter J Campbell, P Andrew Futreal, Michael R Stratton
Affiliations

Signatures of mutation and selection in the cancer genome

Graham R Bignell et al. Nature. .

Abstract

The cancer genome is moulded by the dual processes of somatic mutation and selection. Homozygous deletions in cancer genomes occur over recessive cancer genes, where they can confer selective growth advantage, and over fragile sites, where they are thought to reflect an increased local rate of DNA breakage. However, most homozygous deletions in cancer genomes are unexplained. Here we identified 2,428 somatic homozygous deletions in 746 cancer cell lines. These overlie 11% of protein-coding genes that, therefore, are not mandatory for survival of human cells. We derived structural signatures that distinguish between homozygous deletions over recessive cancer genes and fragile sites. Application to clusters of unexplained homozygous deletions suggests that many are in regions of inherent fragility, whereas a small subset overlies recessive cancer genes. The results illustrate how structural signatures can be used to distinguish between the influences of mutation and selection in cancer genomes. The extensive copy number, genotyping, sequence and expression data available for this large series of publicly available cancer cell lines renders them informative reagents for future studies of cancer biology and drug discovery.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Genomic deletion profile
Deletion patterns in the 746 cancer cell lines across the autosomal chromosomes. The homozygous deletion (red) and small hemizygous deletion (blue) counts are calculated for 100-kb windows across the genome. All homozygous deletion clusters containing six or more homozygous deletions are annotated. Each tick-mark on the vertical axis denotes ten deletions, and the horizontal axis represents each chromosome from p-telomere to q-telomere.
Figure 2
Figure 2. Deletion patterns arising from small and large hemizygous deletions
At any locus each parental chromosome can have one of three deletion states: wild type (W); large deletion (>1 Mb, L); or small deletion (<1 Mb, S). Therefore, in principle, six combinations can exist in a diploid genome: WW, both chromosomes are wild type; WL, one chromosome has a large hemizygous deletion; WS, one chromosome has a small hemizygous deletion; LL, homozygous deletion in which both chromosomes have large overlapping deletions; LS, homozygous deletion in which one chromosome has a large deletion overlapping a small deletion in the other; SS, homozygous deletion in which both chromosomes have small overlapping deletions.
Figure 3
Figure 3. Deletion patterns for clusters of six or more homozygous deletions
Deletion clusters over known fragile sites, over known recessive cancer genes and that are unexplained are shown. The counts for small hemizygous deletions (blue), homozygous deletions arising from two small deletions (orange) and homozygous deletions with at least one large deletion (red) are given for the 100-kb window at the deepest point of each homozygous deletion cluster.
See this image and copyright information in PMC

Similar articles

  • A survey of homozygous deletions in human cancer genomes.
    Cox C, Bignell G, Greenman C, Stabenau A, Warren W, Stephens P, Davies H, Watt S, Teague J, Edkins S, Birney E, Easton DF, Wooster R, Futreal PA, Stratton MR. Cox C, et al. Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4542-7. doi: 10.1073/pnas.0408593102. Epub 2005 Mar 10. Proc Natl Acad Sci U S A. 2005. PMID: 15761058 Free PMC article.
  • Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors.
    Cheng J, Demeulemeester J, Wedge DC, Vollan HKM, Pitt JJ, Russnes HG, Pandey BP, Nilsen G, Nord S, Bignell GR, White KP, Børresen-Dale AL, Campbell PJ, Kristensen VN, Stratton MR, Lingjærde OC, Moreau Y, Van Loo P. Cheng J, et al. Nat Commun. 2017 Oct 31;8(1):1221. doi: 10.1038/s41467-017-01355-0. Nat Commun. 2017. PMID: 29089486 Free PMC article.
  • The oncological relevance of fragile sites in cancer.
    Simpson BS, Pye H, Whitaker HC. Simpson BS, et al. Commun Biol. 2021 May 12;4(1):567. doi: 10.1038/s42003-021-02020-5. Commun Biol. 2021. PMID: 33980983 Free PMC article. Review.
  • A comprehensive catalogue of somatic mutations from a human cancer genome.
    Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Greenman CD, Varela I, Lin ML, Ordóñez GR, Bignell GR, Ye K, Alipaz J, Bauer MJ, Beare D, Butler A, Carter RJ, Chen L, Cox AJ, Edkins S, Kokko-Gonzales PI, Gormley NA, Grocock RJ, Haudenschild CD, Hims MM, James T, Jia M, Kingsbury Z, Leroy C, Marshall J, Menzies A, Mudie LJ, Ning Z, Royce T, Schulz-Trieglaff OB, Spiridou A, Stebbings LA, Szajkowski L, Teague J, Williamson D, Chin L, Ross MT, Campbell PJ, Bentley DR, Futreal PA, Stratton MR. Pleasance ED, et al. Nature. 2010 Jan 14;463(7278):191-6. doi: 10.1038/nature08658. Epub 2009 Dec 16. Nature. 2010. PMID: 20016485 Free PMC article.
  • Large common fragile site genes and cancer.
    Smith DI, McAvoy S, Zhu Y, Perez DS. Smith DI, et al. Semin Cancer Biol. 2007 Feb;17(1):31-41. doi: 10.1016/j.semcancer.2006.10.003. Epub 2006 Oct 26. Semin Cancer Biol. 2007. PMID: 17140807 Review.
See all similar articles

Cited by

  • WWOX: a fragile tumor suppressor.
    Schrock MS, Huebner K. Schrock MS, et al. Exp Biol Med (Maywood). 2015 Mar;240(3):296-304. doi: 10.1177/1535370214561590. Epub 2014 Dec 22. Exp Biol Med (Maywood). 2015. PMID: 25538133 Free PMC article. Review.
  • The genomic landscape of 2,023 colorectal cancers.
    Cornish AJ, Gruber AJ, Kinnersley B, Chubb D, Frangou A, Caravagna G, Noyvert B, Lakatos E, Wood HM, Thorn S, Culliford R, Arnedo-Pac C, Househam J, Cross W, Sud A, Law P, Leathlobhair MN, Hawari A, Woolley C, Sherwood K, Feeley N, Gül G, Fernandez-Tajes J, Zapata L, Alexandrov LB, Murugaesu N, Sosinsky A, Mitchell J, Lopez-Bigas N, Quirke P, Church DN, Tomlinson IPM, Sottoriva A, Graham TA, Wedge DC, Houlston RS. Cornish AJ, et al. Nature. 2024 Sep;633(8028):127-136. doi: 10.1038/s41586-024-07747-9. Epub 2024 Aug 7. Nature. 2024. PMID: 39112709 Free PMC article.
  • The life history of 21 breast cancers.
    Nik-Zainal S, Van Loo P, Wedge DC, Alexandrov LB, Greenman CD, Lau KW, Raine K, Jones D, Marshall J, Ramakrishna M, Shlien A, Cooke SL, Hinton J, Menzies A, Stebbings LA, Leroy C, Jia M, Rance R, Mudie LJ, Gamble SJ, Stephens PJ, McLaren S, Tarpey PS, Papaemmanuil E, Davies HR, Varela I, McBride DJ, Bignell GR, Leung K, Butler AP, Teague JW, Martin S, Jönsson G, Mariani O, Boyault S, Miron P, Fatima A, Langerød A, Aparicio SA, Tutt A, Sieuwerts AM, Borg Å, Thomas G, Salomon AV, Richardson AL, Børresen-Dale AL, Futreal PA, Stratton MR, Campbell PJ; Breast Cancer Working Group of the International Cancer Genome Consortium. Nik-Zainal S, et al. Cell. 2012 May 25;149(5):994-1007. doi: 10.1016/j.cell.2012.04.023. Epub 2012 May 17. Cell. 2012. PMID: 22608083 Free PMC article.
  • Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer.
    Liu W, Lindberg J, Sui G, Luo J, Egevad L, Li T, Xie C, Wan M, Kim ST, Wang Z, Turner AR, Zhang Z, Feng J, Yan Y, Sun J, Bova GS, Ewing CM, Yan G, Gielzak M, Cramer SD, Vessella RL, Zheng SL, Grönberg H, Isaacs WB, Xu J. Liu W, et al. Oncogene. 2012 Aug 30;31(35):3939-48. doi: 10.1038/onc.2011.554. Epub 2011 Dec 5. Oncogene. 2012. PMID: 22139082 Free PMC article.
  • 3D genome organization contributes to genome instability at fragile sites.
    Sarni D, Sasaki T, Irony Tur-Sinai M, Miron K, Rivera-Mulia JC, Magnuson B, Ljungman M, Gilbert DM, Kerem B. Sarni D, et al. Nat Commun. 2020 Jul 17;11(1):3613. doi: 10.1038/s41467-020-17448-2. Nat Commun. 2020. PMID: 32680994 Free PMC article.
See all "Cited by" articles

References

    1. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009;458:719–724. - PMC - PubMed
    1. Pasqualucci L, et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature. 2001;412:341–346. - PubMed
    1. Liu M, et al. Two levels of protection for the B cell genome during somatic hypermutation. Nature. 2008;451:841–845. - PubMed
    1. Rampino N, et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science. 1997;275:967–969. - PubMed
    1. Bader S, et al. Somatic frameshift mutations in the MBD4 gene of sporadic colon cancers with mismatch repair deficiency. Oncogene. 1999;18:8044–8047. - PubMed

Publication types