title: A single-nucleotide substitution mutator phenotype revealed by exome sequencing of human colon adenomas.
abstract: 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.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel-Servet, 1211 Geneva, Switzerland.
authors.forename: Sergey I
authors.initials: SI
authors.lastname: Nikolaev
authors.forename: Sotirios K
authors.initials: SK
authors.lastname: Sotiriou
authors.forename: Ioannis S
authors.initials: IS
authors.lastname: Pateras
authors.forename: Federico
authors.initials: F
authors.lastname: Santoni
authors.forename: Stavros
authors.initials: S
authors.lastname: Sougioultzis
authors.forename: Henrik
authors.initials: H
authors.lastname: Edgren
authors.forename: Henrikki
authors.initials: H
authors.lastname: Almusa
authors.forename: Daniel
authors.initials: D
authors.lastname: Robyr
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.forename: Janna
authors.initials: J
authors.lastname: Saarela
authors.forename: Vassilis G
authors.initials: VG
authors.lastname: Gorgoulis
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Thanos D
authors.initials: TD
authors.lastname: Halazonetis
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004260:DNA Repair / Q000235:genetics; D059472:Exome; D015894:Genome, Human; D042822:Genomic Instability; D006801:Humans; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide