RT Journal Article
SR Electronic
T1 Universal patterns of selection in cancer and somatic tissues
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 132324
DO 10.1101/132324
A1 Iñigo Martincorena
A1 Keiran M. Raine
A1 Moritz Gerstung
A1 Kevin J. Dawson
A1 Kerstin Haase
A1 Peter Van Loo
A1 Helen Davies
A1 Michael R. Stratton
A1 Peter J. Campbell
YR 2017
UL http://biorxiv.org/content/early/2017/04/29/132324.abstract
AB 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