Signatures of mutation and selection in the cancer genome
Open accessAbstract
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. Two Articles in this issue add major data sets to the growing picture of the cancer genome. Bignell et al. analysed a large number of homozygous gene deletions in a collection of 746 publicly available cancer cell lines. Combined with information about hemizygous deletions of the same genes, the data suggest that many deletions found in cancer reflect the position of a gene at a fragile site in the genome, rather than as a recessive cancer gene whose loss confers a selective growth advantage. Beroukhim et al. present the largest data set to date on somatic copy-number variations across more than 3,000 specimens of human primary cancers. Many alterations are shared between multiple tumour types. Functional experiments demonstrate an oncogenic role for the apoptosis genes MCL1 and BCL2L1 that are associated with amplifications found in many cancers. Homozygous gene deletions in cancer cells occur over recessive cancer genes (where they can confer selective growth advantage) or over genes at fragile sites of the genome (where they are thought to reflect increased DNA breakage). Here, a large number of homozygous deletions in a collection of cancer cell lines are identified and analysed to derive structural signatures for the two different types of deletion. More deletions are found in inherently fragile regions, and fewer overlying recessive genes.
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“tandem repeat-containing regions we identified co-localized to 9 of 11 (81.8%) of the molecularly mapped rare folate-sensitive fragile sites37, all at CG-containing tandem repeats”
From Genome-wide detection of tandem DNA repeats that are expanded in autism (2020) · cites this paper as [37]
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- Authors
- Bignell, G. R., Greenman, C. D., Davies, H., Butler, A. P., Edkins, S., Andrews, J. M., Buck, G., Chen, L., Beare, D., Latimer, C., Widaa, S., Hinton, J., Fahey, C., Fu, B., Swamy, S., Dalgliesh, G. L., Teh, B. T., Deloukas, P., Yang, F., Campbell, P. J., Futreal, P. A., & Stratton, M. R.
- Affiliations
- Wellcome Sanger Institute (GB)
- Van Andel Institute (US)
- Institute of Cancer Research (GB)
- Corresponding author
- Futreal, P. Andrew
- Stratton, Michael R.
- ORCID
- Venue
- Nature
- Published
- 2010-02
- Volume
- 463
- Issue
- 7283
- Pages
- 893-898
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3145113
- OpenAlex
- W2071734901
- Cited by
- 707
- References
- 41
- Citations by year
- 2026: 7 · 2025: 24 · 2024: 21 · 2023: 29 · 2022: 25 · 2021: 32 · 2020: 40 · 2019: 30 · 2018: 44 · 2017: 44 · 2016: 47 · 2015: 48 · 2014: 61 · 2013: 71 · 2012: 76
- FWCI
- 25.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- Wellcome Trust (077012/Z/05/Z, 088340, 093867)
- National Cancer Institute (P01CA155258)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- fragile sites, copy number variation, cancer cell lines, structural signatures, DNA breakage, Mcl-1, Bcl-xL, gene amplification, tumor suppressor
- MeSH terms
- Chromosomes, Human, DNA Mutational Analysis, Genes, Recessive, Homozygote, Humans, Models, Genetic, Neoplasms, Selection, Genetic, Reproducibility of Results, Genome, Human, Gene Deletion, Gene Dosage, Physical Chromosome Mapping, Oligonucleotide Array Sequence Analysis, Chromosome Fragile Sites, Cell Line, Tumor, Genes, Neoplasm, DNA Copy Number Variations
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