The recent cloning of a breast-ovarian cancer susceptibility gene (BRCA1), and determination of the locus of a related gene (BRCA2), offers potential for clinical genetic testing for breast cancer susceptibility.
The breast cancer susceptibility gene BRCA1 has been cloned and a second susceptibility gene, BRCA2, chromosomally mapped; will most breast and ovarian cancer turn out to be familial?
Preliminary evidence suggests that BRCA2 confers a high risk of breast cancer but, unlike BRCA1, does not confer a substantially elevated risk of ovarian cancer.
Our results suggest that BRCA2 is a very infrequent target for somatic inactivation in breast and ovarian carcinomas, similar to the results obtained for BRCA1.
Unlike BRCA1, however, which confers a high risk to both breast and ovarian cancer, the incidence of ovarian cancer appears to be much lower In BRCA2-linked families, causing uncertainty as to the relevance of BRCA2 to hereditary ovarian cancer.
The same BRCA2 mutation appears to be associated with different cancer phenotypes in this population including male and female breast cancer, prostate cancer, pancreas cancer and ovarian cancer.
A role for BRCA2 in sporadic breast and ovarian cancer has been suggested by loss of heterozygosity (LOH) studies which show frequent LOH in the BRCA2 region at chromosome 13q12.
Our results indicate that BRCA2 confers a very high risk of breast cancer and is responsible for a substantial fraction of breast and ovarian cancer in Iceland, but only a small proportion of other cancers.
Recent studies have identified mutations in the breast and (ovarian cancer susceptibility gene 2 (BRCA2), one which has been found in the germline of several males and one female affected with breast cancer.
BRCA2 carries a risk of breast cancer similar to that of BRCA1, but is associated with a lower risk of ovarian cancer and a higher risk of male breast cancer.
Germline mutations of BRCA2 are predicted to account for approximately 35% of families with multiple case, early onset female breast cancer, and they are also associated with an increased risk of male breast cancer, ovarian cancer, prostate cancer and pancreatic cancer.
Only one of the two male breast cancer patients carrying a BRCA2 mutation had a family history of cancer, with one case of ovarian cancer in a first-degree relative.
The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women.
Most multiple case families of young onset breast cancer and ovarian cancer are thought to be due to highly penetrant mutations in the predisposing genes BRCA1 and BRCA2.
Germline mutations of BRCA1 are also associated with ovarian cancer and mutations of BRCA2 are associated with an increased risk of male breast cancer, ovarian cancer, prostate cancer and pancreatic cancer.
These BRCA2 families have early-onset breast cancer (mean and median age = 49 years), with four of the eight families including ovarian cancer but with no families including male breast cancer.
Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families.
The breast carcinoma genes BRCA1 and BRCA2 have been linked to familial and sporadic forms of breast cancer and ovarian cancer, providing an opportunity to test this clinical observation.