Cancer cells evolve from normal cells by somatic mutations and natural 
selection. Comparing the evolution of cancer cells and that of organisms can 
elucidate the genetic basis of cancer. Here we analyse somatic mutations in >400 
cancer genomes. We find that the frequency of somatic single-nucleotide 
variations increases with replication time during the S phase much more 
drastically than germ-line single-nucleotide variations and somatic large-scale 
structural alterations, including amplifications and deletions. The ratio of 
nonsynonymous to synonymous single-nucleotide variations is higher for cancer 
cells than for germ-line cells, suggesting weaker purifying selection against 
somatic mutations. Among genes with recurrent mutations only cancer driver genes 
show evidence of strong positive selection, and late-replicating regions are 
depleted of cancer driver genes, although enriched for recurrently mutated 
genes. These observations show that replication timing has a prominent role in 
shaping the single-nucleotide variation landscape of cancer cells.