TY - JOUR T1 - Universal patterns of selection in cancer and somatic tissues JF - bioRxiv DO - 10.1101/132324 SP - 132324 AU - Iñigo Martincorena AU - Keiran M. Raine AU - Moritz Gerstung AU - Kevin J. Dawson AU - Kerstin Haase AU - Peter Van Loo AU - Helen Davies AU - Michael R. Stratton AU - Peter J. Campbell Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/04/29/132324.abstract N2 - Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We applied methods from evolutionary genomics to 7,664 human cancers across 29 tumor 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 only detected for truncating mutations in essential genes in haploid regions. This allows exome-wide enumeration of all driver 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 identify novel cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.HIGHLIGHTSUnlike the germline, somatic cells evolve predominantly by positive selectionNearly all (∼99%) coding mutations are tolerated and escape negative selectionFirst exome-wide estimates of the total number of driver coding mutations per tumor1-10 coding driver mutations per tumor; half occurring outside known cancer genes ER -