Breast-Ovarian Cancer, Familial, Susceptibility To, 3

A number sign (#) is used with this entry because susceptibility to familial breast-ovarian cancer-3 (BROVCA3) results from heterozygous germline mutation in the RAD51C gene (602774) on chromosome 17q21-q24.

For a discussion of genetic heterogeneity of breast-ovarian cancer susceptibility, see BROVCA1 (604370).

For general discussions of breast cancer and ovarian cancer, see 114480 and 167000, respectively.

Meindl et al. (2010) identified 6 unrelated German pedigrees with breast-ovarian cancer associated with heterozygous germline mutations in the RAD51C gene. Each family had at least 2 affected women. The mean age of onset was 53 years (range 33 to 78) for breast cancer and 60 years (range 50 to 81) for ovarian cancer. These ages are higher than the mean ages of 40 and 46 years for German BROVCA1 and BROVCA2 (612555) breast cancers, respectively, although lower than the mean age of 63 years for sporadic breast cancer. For ovarian cancer, the mean age of onset in individuals carrying BRCA1 (113705) or BRCA2 (600185) mutations and for the general population is 49, 58, and 68 years, respectively. None of the families with RAD51C mutations had male breast cancer patients. The segregation pattern in BROVCA3 was striking and complete: none of the tested healthy females over 70 years of age inherited the mutations, and all affected first-degree relatives who developed malignancies were mutation carriers. Pathology reports available from 11 cases of breast cancer showed that 10 were invasive ductal carcinomas; 1 was a preinvasive ductal carcinomas. Estrogen (ESR1; 133430) and progesterone (PGR; 607311) receptor status was variable; all tumors were negative for HER2/neu (164870). These findings indicated that RAD51C-associated breast cancer is distinct from BRCA1-associated breast cancer and might be associated with more favorable histopathologic features like those of BRCA2-associated breast cancer. Pathology reports available from 7 ovarian cancers showed that 6 were invasive serous adenocarcinomas and 1 was an invasive endometrioid adenocarcinoma.

Meindl et al. (2010) identified 6 different monoallelic (heterozygous) pathogenic mutations in the RAD51C gene (e.g., 602774.0002-602774.0004) in 6 (1.3%) of 480 unrelated women from pedigrees with breast and ovarian cancer. There were 2 frameshift insertions, 2 splice-site mutations, and 2 nonfunctional missense mutations. RAD51C mutations were not found in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. Analysis of tumor tissue showed loss of heterozygosity at the RAD51C locus, and in vitro studies showed that the mutant proteins were unable to restore normal RAD51C activity to RAD51C-deficient cells. These findings were consistent with RAD51C acting as a tumor suppressor gene. Meindl et al. (2010) concluded that the results supported the 'common disease, rare allele' hypothesis for cancer.

Pelttari et al. (2011) identified 2 recurrent mutations in the RAD51C gene (602774.0007 and 602774.0008) in Finnish patients with breast-ovarian cancer. The mutations associated with an increased risk of familial breast and ovarian cancer (odds ratio (OR) of 13.59; p = 0.026 compared to controls), but especially with familial ovarian cancer in the absence of breast cancer (OR of 213; p = 0.0002). The mutations also associated with unselected ovarian cancer (OR of 6.31; p = 0.033), but there was a significantly higher mutation rate among the familial cases. However, no mutations were found among cases with familial breast cancer only, and the mutation frequency among all breast cancer cases was not different from controls. The results suggested that RAD51C is a moderate to high risk susceptibility gene for ovarian cancer.

Thompson et al. (2012) identified 2 truncating mutations in the RAD51C gene (see, e.g., 602774.0005) in 2 of 335 families with breast-ovarian cancer or ovarian cancer only. One of 267 additional patients with ovarian cancer was found to carry another truncating mutation (602774.0006). No RAD51C mutations were found in 1,053 families with breast cancer only. The findings suggested a low frequency (less than 1%) of RAD51C mutations in families with increased risk of ovarian cancer, particularly in the context of breast cancer.

Among 1,132 probands from families with a history of ovarian cancer occurring with or without breast cancer and 272 individuals with ovarian cancer from a hospital-based unselected case series, Loveday et al. (2012) identified 12 truncating mutations in the RAD51C gene. Nine of the mutations occurred in familial cases, but segregation with disease was not proven in any of the families. One mutation was also found in 1 of 1,156 controls. The relative risk of ovarian cancer for RAD51C mutation carriers was estimated to be 5.88 (p = 7.65 x 10(-7)). In contrast, there was no evidence of an association with breast cancer (relative risk = 0.91, p = 0.8).