These results suggest that mutation of BRCA1 may not be critical in the development of the majority of breast and ovarian cancers that arise in the absence of a mutant germline allele.
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.
These data are consistent with the hypothesis that BRCA1 mutations are involved in the etiology of hereditary ovarian carcinomas but occur rarely in sporadic tumors, and that the frequent allelic loss on chromosome 17q in this cancer type reflects the involvement of an additional tumor suppressor gene(s).
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.
In the context of high-risk families the most important genes are BRCA1 on chromosome 17q, which is associated with a high penetrance of both breast and ovarian cancer, and BRCA2 on chromosome 13q, which causes a high risk of breast cancer but a lower risk of ovarian cancer.
Since allelic loss has been reported in the 17q12-q21 region in breast and ovarian cancer and it appears that BRCA1 is not the target of the losses, we looked for somatic alterations in DLG2 in sporadic breast tumors.
The majority of multiple-case families that segregate both breast and ovarian cancer in a dominant fashion are due to mutations in the BRCA1 gene on chromosome 17q.
Our data support a tumour suppressor mechanism for BRCA1; somatic mutations and LOH may result in inactivation of BRCA1 in at least a small number of ovarian cancers.
Given the expected logistical problems in clinical management now that BRCA1 has been identified, we propose an interim period in which only families with a strong positive family history for early onset breast and/or ovarian cancer will be offered BRCA1 mutation testing.
Additionally, efforts using this methodology to generate a microclone library encompassing the early onset breast/ovarian cancer (BRCA1) gene will be presented.
The risk of ovarian cancer decreased with increasing age at last childbirth; however, in contrast to the case for sporadic cancer, the risk of ovarian cancer in BRCA1 carriers was found to increase significantly with increasing parity.
This method has been applied to chromosome bands 17q12-q21, a region that includes a gene (BRCA1) involved in early onset familial breast and ovarian cancer.
It is estimated that women harboring a germline BRCA1 mutation incur an 85% lifetime risk of breast cancer and a greatly elevated risk of ovarian cancer.
The older age of onset in cases in which allele loss was seen only in the ovarian cancer suggests that the development of these cancers is not related to an inherited defect in BRCA1.