Heterogenous point mutations in the BRCA1 breast cancer susceptibility gene occur in high frequency at the site of homonucleotide tracts, short repeats and methylatable CpG/CpNpG motifs.
Heterogeneous mutations in the BRCA1 tumour suppressor gene are responsible for a large percentage of inherited breast cancers as well as breast/ovarian cancers in families with a high incidence of both cancer types. Over a hundred BRCA1 mutations have been reported, but little is known of the mechanism(s) responsible for BRCA1 mutagenesis. To determine the significance of specific nucleotide sequences at mutational sites within the BRCA1 gene, we assessed how frequently independent BRCA1 mutations occur at the site of short direct repeats, single nucleotide repeats (homonucleotides) and at CpG and CpNpG motifs. We found that homonucleotide and short direct repeats are commonly associated with small deletions and insertions. Substitution mutations are frequently associated with homonucleotide repeats and with methylatable CpG dinucleotides and CpNpG trinucleotides. Our methylation and sequencing experiments show that CpG and certain CpNpG motifs are methylated, supporting the hypothesis that DNA methylation specificity at these sites may be an important contributor to BRCA1 mutagenesis. We suggest that BRCA1 mutations are acquired by replication errors and are retained by cells through an intricate balancing of replication and repair mechanisms. Such mutations may provide a proliferative advantage for a cell, leading to the tumour phenotype.
Rodenhiser
D
D
Molecular Medical Genetics Program, Child Health Research Institute, Children's Hospital of Western Ontario, Canada.
Chakraborty
P
P
Andrews
J
J
Ainsworth
P
P
Mancini
D
D
Lopes
E
E
Singh
S
S
D019313:BRCA1 Protein; D001482:Base Composition; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D018899:CpG Islands; D004251:DNA Transposable Elements; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008745:Methylation; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides; D017354:Point Mutation; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D018911:Trinucleotide Repeats
D019313:BRCA1 Protein; D004251:DNA Transposable Elements; D009363:Neoplasm Proteins; D009838:Oligodeoxyribonucleotides; D014157:Transcription Factors