HETEROGENEOUS 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 respon sible for a large percentage of inherited breast cancers as well as br east/ovarian cancers in families with a high incidence of both cancer types, Over a hundred BRCA1 mutations have been reported, but little i s known of the mechanism(s) responsible for BRCA1 mutagenesis, To dete rmine the significance of specific nucleotide sequences at mutational sites within the BRCA1 gene, are assessed how frequently independent B RCA1 mutations occur at the site of short direct repeats, single nucle otide repeats (homonucleotides) and at CpG and CpNpG motifs, We found that homonucleotide and short direct repeats are commonly associated w ith small deletions and insertions, Substitution mutations are frequen tly associated with homonucleotide repeats and with methylatable CpG d inucleotides and CpNpG trinucleotides, Our methylation and sequencing experiments show that CpG and certain CpNpG motifs are methylated, sup porting 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 b y cells through an intricate balancing of replication and repair mecha nisms, Such mutations may provide a proliferative advantage for a cell , leading to the tumour phenotype.