title: CpG/CpNpG motifs in the coding region are preferred sites for mutagenesis in the breast cancer susceptibility genes.
abstract: The range of BRCA1/BRCA2 gene mutations is diverse and the mechanism accounting for this heterogeneity is obscure. To gain insight into the endogenous mutational mechanisms involved, we evaluated the association of specific sequences (i.e. CpG/CpNpG motifs, homonucleotides, short repeats) and mutations within the genes. We classified 1337 published mutations in BRCA1 (1765 BRCA2 mutations) for each specific sequence, and employed computer simulation combined with mathematical calculations to estimate the true underlying tendency of mutation occurrence. Interestingly, we found no mutational bias to homonucleotides and repeats in deletions/insertions and substitutions but striking bias to CpG/CpNpG in substitutions in both genes. This suggests that methylation-dependent DNA alterations would be a major mechanism for mutagenesis.
authors.affiliation: School of Biological Sciences, University of Hong Kong, Hong Kong.
authors.forename: Lydia W T
authors.initials: LW
authors.lastname: Cheung
authors.forename: Yiu Fai
authors.initials: YF
authors.lastname: Lee
authors.forename: Tuen Wai
authors.initials: TW
authors.lastname: Ng
authors.forename: Wai Ki
authors.initials: WK
authors.lastname: Ching
authors.forename: Ui Soon
authors.initials: US
authors.lastname: Khoo
authors.forename: Michael K P
authors.initials: MK
authors.lastname: Ng
authors.forename: Alice S T
authors.initials: AS
authors.lastname: Wong
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D003198:Computer Simulation; D020862:GC Rich Sequence; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D016296:Mutagenesis / Q000235:genetics*; D016366:Open Reading Frames / Q000235:genetics*