Cell
Volume 171, Issue 5, 16 November 2017, Pages 1029-1041.e21
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Article
Universal Patterns of Selection in Cancer and Somatic Tissues

https://doi.org/10.1016/j.cell.2017.09.042Get rights and content
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Highlights

  • Unlike the germline, somatic cells evolve predominantly by positive selection

  • Nearly all (∼99%) coding mutations are tolerated and escape negative selection

  • Exome-wide estimates of the total number of driver coding mutations per tumor

  • Half of the coding driver mutations occur outside of known cancer genes

Summary

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
genomics
evolution
mutations
selection

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