Cancer prevalence in 129 breast-ovarian cancer families tested for BRCA1 and BRCA2 mutations

Abstract

Breast cancer is the most common malignancy among women in South Africa, with a crude incidence rate of 18.5/100 000 recorded between 1993 and 1995.1 A small but significant percentage (5 -10%) of breast cancer cases are directly due to an inherited susceptibility.2 Two tumour suppressor genes involved in early-onset breast and ovarian cancer, BRCA1 and BRCA2, have been mapped and cloned. 3,4 These two genes explain 20 -40% of heritable breast cancer cases in various populations over the world. 5,6 A large linkage and mutation study on 237 families collected by the Breast Cancer Linkage Consortium found that overall BRCA1 accounts for 52% of all families, and BRCA2 for 32%, leaving 16% of the families with a familial breast cancer phenotype unaccounted for. 7 In the study, 81% of the families with both a breast and an ovarian phenotype were BRCA1-positive families while 14% linked to BRCA2. The situation was reversed in families that presented with a male breast cancer phenotype in addition to female breast cancer, where 76% linked to BRCA2 and only a small percentage to BRCA1.Worldwide many families with a strong history of familial breast cancer have been fully screened for BRCA1 and BRCA2 mutations but none were found. This is especially the case in breast cancer-specific families (no other cancers beside breast cancer in family). While the search for the BRCA1 and BRCA2 genes was helped by the strong association of ovarian cancer in addition to breast cancer with BRCA1 and male breast cancer with BRCA2, the search for other breast cancer-associated genes is more complicated. Studies on BRCA1-and 2-negative breast cancer families showed that the most probable explanation is that there are multiple additional genes with lower penetrance and/or prevalence, each responsible for a small number of families. 8,9

Screening for gynaecologic cancers in genetically predisposed women

“…Some cancer incidence studies have found a significantly increased risk for a variety of other cancers, including stomach, pancreatic and melanoma [10]. Differences between the results suggest population and mutation specificity.…”

“…In most studies the family members of mutation positive women reported a significantly higher incidence of uterine cancer than the probands of mutation negative women [10]. One large study based on family history of 11 000 women, reports the risk for uterine cancer as 2.65 times the background population risk [51] Although many case reports of uterine and uterine papillary serous carcinoma (UPSC) in mutation positive women have been published and women diagnosed with UPSC seem to have a family history suggestive of HBOC more often than expected [55], the risk in genetically predisposed women to develop these cancers seem relatively low.…”

“…Blood levels of current markers only increase less than a year before symptoms [31] Also, improved imaging must lead to less diagnostic operations for benign disease. One option is to add sonographic measurement of ovarian volume and use normal values adjusted for age [10]. Three-dimensional power Doppler evaluation may also aide diagnostic accuracy [69].…”

“…[11] Specifically families displaying an excess of breast cancer only, will often not harbour a BRCA mutation [10]. The other involved genetic factors may be recessive (as suggested by the excess in sibling compared to offspring risk), or may be dominant but with a smaller penetrance than the BRCA genes [12].…”

“…The prevalence of BRCA mutations differs per population group and many groups display a founder effect, enabling cheaper meaningful gene testing [9,10].…”