Signatures of mutation and selection in the cancer genome

By G. Bignell, C. Greenman, Helen R. Davies, Adam P. Butler, S. Edkins, J. Andrews, Gemma Buck, Lina Chen, D. Beare, Calli Latimer and 12 more. Nature, 2010

715 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/53aab9ec3add5b078bc3ca6c6e91371760dec643

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Citations in the corpus

Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development (2011, methodology): “To assess whether the unusual genomic landscape observed in the patient with CLL could be seen in other cancer samples, we analyzed high-resolution copy number profiles of 746 cancer cell lines obtained using SNP arrays (Bignell et al., 2010).”
GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers (2011, background): “Dramatic improvements in both array and sequencing platforms have enabled increasingly high-resolution characterization of the SCNAs present in thousands of cancer genomes [4-6].”
Guidelines for the welfare and use of animals in cancer research (2010, background): “…of human cells Human cancer cell lines are increasingly being characterised by genetic and other molecular techniques (Ihle et al, 2009; Bignell et al, 2010) Can be an established cell line or human primary tissue (Neale et al, 2008; Rubio-Viqueira and Hidalgo, 2009) Amenable for…”
DNA replication stress as a hallmark of cancer. (2015, background): “Further, whereas the deletions targeting well-established tumor suppressor genes are typically homozygous, the deletions targeting very large genes are typically hemizygous and, thus, a wild-type copy of the gene is retained (9).”
Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer. (2018, neutral): “This analysis also identified clusters of deletions affecting genes at fragile sites previously identified in more than one cancer type (Bignell et al., 2010; Glover et al., 2017).”
The Life History of 21 Breast Cancers (2012, neutral): “Trisomy 1q is one of the commonest copy number alterations seen in breast cancer (Beroukhim et al., 2010; Bignell et al., 2010).”