Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families

Abstract

Women who carry mutations in the BRCA1 gene on chromosome 17q have an 85% lifetime risk of breast cancer, and a 60% risk of ovarian cancer. We have identified BRCA1 mutations in 12 of 30 (40%) Canadian families with breast and/or ovarian cancer, including six of the eight families (75%) that contained two cases of early-onset breast cancer and two cases of ovarian cancer. Six frameshift mutations account for all 12 mutant alleles, including nucleotide insertions (two mutations) and deletions (four mutations). Four independent families carried the same 1 basepair (bp) insertion mutation in codon 1755 and four other families shared a 2 bp deletion mutation in codons 22-23. These families were not known to be related, but haplotype analysis suggests that the carriers of each of these mutations have common ancestors.

BRCA1 5382insC mutation in sporadic and familial breast and ovarian carcinoma in Scotland

“…Using the convention for describing allele sizes established by Simard et al (1994), our positive sample had the haplotype D/A for D17S855, E/E for D17S1322, F/F for D17S1323 and O/M for D17S1327. Haplotyping carried out with five affected members of the West Lothian kindred along with BC185 revealed a 2-bp difference between BC185 (DEFO) and all five kindred members (DEFN).…”

“…The BRCAJ 5382insC mutation has been widely reported (Castilla et al, 1994;Friedman et al, 1994;Gayther et al, 1995), including a study of four apparently unrelated Canadian families (Simard et al, 1994). Each of these families shared a common haplotype around the BRCAJ gene and are thus thought to be of the same ancestral mutation.…”

“…Furthermore, 80-90% of families in which two or more cases of early onset breast cancer and two or more cases of ovarian cancer occur carry BRCAJ mutations (Easton et al, 1993; Narod et al, 1995). Such genetic predispositions are thought to be responsible for between 5% and 10% of all females with breast cancer (Newman et al, 1988;Claus et al, 1991).The BRCAJ 5382insC mutation has been widely reported (Castilla et al, 1994;Friedman et al, 1994;Gayther et al, 1995), including a study of four apparently unrelated Canadian families (Simard et al, 1994). Each of these families shared a common haplotype around the BRCAJ gene and are thus thought to be of the same ancestral mutation.…”

Identification of a BRCA1-associated kinase with potential biological relevance

“…Studies conducted to date show that mutations in BRCA1 occur frequently in families demonstrating a high incidence of breast and/or ovarian cancer (Castilla et al, 1994;Miki et al, 1994;Friedman et al, 1994;Shattuck-Eidens et al, 1995;Simard et al, 1994). Notably, women within such families who develop cancer all have inherited the mutant allele and have also acquired a somatic mutation a ecting the other allele (Castilla et al, 1994;Merajver et al, 1995;Smith et al, 1992).…”

Breaking down BRCA1

“…4. The 5382insC mutation may be associated with a wide range of different cancers\ but there is no obvious relationship between mutation position and phenotypes.…”