Oncogene-induced DNA replication stress is thought to drive genomic instability 
in cancer. In particular, replication stress can explain the high prevalence of 
focal genomic deletions mapping within very large genes in human tumors. 
However, the origin of single-nucleotide substitutions (SNS) in nonfamilial 
cancers is strongly debated. Some argue that cancers have a mutator phenotype, 
whereas others argue that the normal DNA replication error rates are sufficient 
to explain the number of observed SNSs. Here, we sequenced the exomes of 24, 
mostly precancerous, colon polyps. Analysis of the sequences revealed mutations 
in the APC, CTNNB1, and BRAF genes as the presumptive cancer-initiating events 
and many passenger SNSs. We used the number of SNSs in the various lesions to 
calculate mutation rates for normal colon and adenomas and found that colon 
adenomas exhibit a mutator phenotype. Interestingly, the SNSs in the adenomas 
mapped more often than expected within very large genes, where focal deletions 
in response to DNA replication stress also map. We propose that single-stranded 
DNA generated in response to oncogene-induced replication stress compromises the 
repair of deaminated cytosines and other damaged bases, leading to the observed 
SNS mutator phenotype.