Τίτλος:
A single-nucleotide substitution mutator phenotype revealed by exome sequencing of human colon adenomas
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. ©2012 American Association for Cancer Research.
Συγγραφείς:
Nikolaev, S.I.
Sotiriou, S.K.
Pateras, I.S.
Santoni, F.
Sougioultzis, S.
Edgren, H.
Almusa, H.
Robyr, D.
Guipponi, M.
Saarela, J.
Gorgoulis, V.G.
Antonarakis, S.E.
Halazonetis, T.D.
Περιοδικό:
Current Cancer Research
Λέξεις-κλειδιά:
APC protein; B Raf kinase, APC gene; article; Braf gene; colon adenoma; colon polyp; controlled study; CTNNB1 gene; DNA replication; exome; gene; gene deletion; gene mapping; gene mutation; gene sequence; genomic instability; human; human tissue; mutation rate; mutator phenotype; nucleic acid base substitution; priority journal; single nucleotide substitution, Adenoma; Colorectal Neoplasms; DNA Repair; Exome; Genome, Human; Genomic Instability; Humans; Mutation; Phenotype; Polymorphism, Single Nucleotide
DOI:
10.1158/0008-5472.CAN-12-3869
