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Breast cancer is one of the most common malignancies in women, affecting one in twelve. Ovarian cancer, although not as frequent, is the leading cause of death from gynaecological cancer. Inherited predisposition to breast and ovarian cancer, which accounts for approximately 5 to 10% of these cancers, has been associated with mutations in the BRCA1 and BRCA2 genes. Mutations in both of these genes increase the lifetime risk of developing breast cancer by approximately 80%. BRCA1 confers a greater predisposition of ovarian cancer than BRCA2, however, BRCA2 has been associated with male breast cancer. Polymorphisms linked to BRCA1 and BRCA2 were studied to examine whether either of these genes were linked to breast and breast/ovarian cancer families. None of the five cancer families studied generated statistically significant lod scores although the segregation of a common haplotype with the disease in each family and positive lod scores did suggest that four of these families were linked to BRCA1 and the other to BRCA2. Subsequent mutation studies identified three germline mutations, thus confirming the initial linkage results in three families. A total of four deletions and six polymorphisms were identified in BRCA1 and BRCA2 from forty-eight breast and breast/ovarian cancer families, using SSCP analysis and PTT. The functional effect of these mutations is unclear although variable expression of the cancer phenotype suggests that other genes and environmental factors play an important role in the development of breast and ovarian cancer. Evidence of an abnormal protein was detected by the presence of clonal LOH of the normal allele, using BRCA1 antibodies in familial breast and ovarian tumours. In addition, BRCA1 immunostaining was negative in a greater proportion of benign tumours compared to malignant ovarian tumours. The loss of BRCA1 does not lead to malignancy, suggesting that BRCA1 may have another role in benign ovarian epithelial tumours. |
