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Cell. 2017 Nov 16;171(5):1029-1041.e21. doi: 10.1016/j.cell.2017.09.042. Epub 2017 Oct 19.

Universal Patterns of Selection in Cancer and Somatic Tissues.

Author information

1
Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK. Electronic address: im3@sanger.ac.uk.
2
Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.
3
European Molecular Biology Laboratory, European Bioinformatics Institute EMBL-EBI, Hinxton CB10 1SD, UK.
4
The Francis Crick Institute, London NW1 1AT, UK.
5
The Francis Crick Institute, London NW1 1AT, UK; Department of Human Genetics, University of Leuven, Leuven 3000, Belgium.
6
Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK; Department of Haematology, University of Cambridge, Cambridge CB2 2XY, UK. Electronic address: pc8@sanger.ac.uk.

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

PMID:
29056346
PMCID:
PMC5720395
DOI:
10.1016/j.cell.2017.09.042
[Indexed for MEDLINE]
Free PMC Article

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