Journal
CELL
Volume 171, Issue 5, Pages 1029-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2017.09.042
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Funding
- EMBO [aALTF 766-2015]
- Cancer Research UK [C57387/A21777, FC001202]
- Wellcome Trust [FC001202]
- Francis Crick Institute
- UK Medical Research Council [FC001202]
- Cancer Research UK [21777] Funding Source: researchfish
- The Francis Crick Institute [10202] Funding Source: researchfish
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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 similar to 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.
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