Journal Article

Signatures of mutation and selection in the cancer genome

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

2010

Overview

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. Cancer genomics refined 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/69 / 631/208/737 / 631/535 / Biological and medical sciences / Biology / Breast cancer / Cancer / Carcinogenesis / Cell Line, Tumor / Chromosome Fragile Sites - genetics / Chromosomes, Human - genetics / Deletion / DNA Copy Number Variations - genetics / DNA Mutational Analysis / Fragility / Gene Deletion / Gene Dosage - genetics / Gene expression / Gene mutations / Genes / Genes, Neoplasm - genetics / Genes, Recessive - genetics / Genetic aspects / Genetics / Genome, Human - genetics / Genomes / Health aspects / Homozygote / Humanities and Social Sciences / Humans / Medical sciences / Models, Genetic / multidisciplinary / Multiple tumors. Solid tumors. Tumors in childhood (general aspects) / Mutation / Mutations / Neoplasms - genetics / Oligonucleotide Array Sequence Analysis / Physical Chromosome Mapping / Reagents / Reproducibility of Results / Risk factors / Science / Selection, Genetic - genetics / Signatures / Studies / Tissues / Tumors