Other Types of Cancer Associated with Mutations in BRCA2
BRCA2 mutations are associated with elevated risks for the development of a variety of other cancers. Higher than expected rates of prostate cancer, pancreatic cancer, non-Hodgkin’s lymphoma, basal cell carcinoma, fallopian tube tumors, and bladder carcinoma have been reported in association with BRCA2 mutations. However, the full spectrum of cancers associated with BRCA2 remains poorly defined.

One approach to defining the risk of other cancers associated with BRCA1 and BRCA2 mutations is the study of women with multiple primary cancers. In the initial report of such a study, 63 women with multiple primary cancers (of which one was breast cancer) were analyzed for BRCA1 and BRCA2 mutations. Seven (17.9%) of the 39 women with breast cancer and a nonovarian second primary cancer had either a BRCA1 or BRCA2 mutation. Second cancers included two cases of unspecified skin cancers; a single case each of uterine leiomyosarcoma, brain cancer, bladder cancer, leukemia;and both thyroid and colon cancer in one proband. Overall, 29 (46%)of 63 families screened had a mutation in either the BRCA1 or BRCA2 gene. These data suggest that cancer susceptibility in general is increased in carriers of these mutations.

Pathobiology of BRCA2-Associated Breast Cancer
One study found that, unlike BRCA1-associated tumors, BRCA2-associated tumors are similar to sporadic tumors in the number of mitoses, degree of pleomorphism, and proportion classified as medullary. In this study, the proportion of tubular carcinomas was significantly lower in the BRCA2-associated group than the sporadic group, whereas rates of invasive ductal carcinoma, invasive lobular carcinoma, and ductal carcinoma in situ were no different in the BRCA2-associated and the sporadic groups.

However, other researchers who compared 85 cases presumed to be BRCA2-related (familial, BRCA1 negative) with 90 BRCA1-confirmed cases and 187 sporadic cases found that the BRCA2 group had a significantly greater proportion of tubular cancers. Little is known yet about the natural history of breast cancer due to BRCA2 mutations; prospective longitudinal studies are under way to attempt to address this question.

BRCA2 Gene Structure and Mutation Spectrum
The coding region of BRCA2 is 11.2 kb in length and is comprised of 26 exons. This is approximately twice as large as BRCA1, itself one of the largest genes isolated to date. This size adds to the difficulties associated with mutation analysis in both the clinical and research settings. Unlike BRCA1, the genomic region of BRCA2 is not rich in repetitive elements, and genomic deletions as the underlying basis of disease-associated germ-line BRCA2 mutations have not been described.

Like BRCA1, BRCA2 is expressed in most tissues at very low levels, with higher expression in testis and thymus. BRCA2 cDNA has no significant homology to any previously described gene, and the protein contains no previously defined functional domains. However, eight copies of a 30- to 80-amino-acid repeat (BRC repeat) are encoded by exon 11. The functional significance of the conserved repeats remains controversial, but at least some of the repeats form the binding site for the interaction between BRCA2 and Rad51.

More than 250 BRCA2 mutations have been identified to date. A tabulated list of these mutations can be found on the BIC website. Interestingly, several simiarities with BRCA1 are apparent. First, BRCA2 mutations span the entire coding region of the gene, adding little information on important functional regions and making mutation screening difficult in this very large gene. No mutation hot spots have been detected. Second, most mutations reported to date are truncating mutations, again adding little in the way of clues for defining functional regions. Finally, as with BRCA1, few mutations have been identified in the BRCA2 gene in sporadic breast or ovarian cancers, suggesting that mutations in coding regions in BRCA2 do not play a role in sporadic breast cancer pathogenesis.

Several founder mutations have been identified in the BRCA2 gene in specific populations. As discussed previously, the 6174delT mutation has been found in the Ashkenazi Jewish population at a prevalence of 1.2%, with more than 2.5% of the entire Ashkenazi Jewish population now thought to carry one of three specific BRCA1 and BRCA2 mutations. No cases of patients carrying two mutated copies of BRCA2 have been reported, which suggests that this combination may be incompatible with life. However, several groups have reported patients found to have one BRCA1 mutation and one BRCA2 mutation (unpublished data, Breast Cancer Linkage Consortium meeting, 1997).