BRCA 1 and 2--A Genetic Link to Familial Breast and Ovarian Cancer

, , , Duke University Medical Center

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BRCA1 was estimated to be responsible for approximately 45% of breast cancer families and for the majority of breast/ovarian cancer families.[18] A proportion of breast cancer families not linked to BRCA1 were found to be linked to a second locus on chromosome 13q12-13.[43] It was postulated that the majority of remaining breast cancer families would also be due to mutations in this gene. The new gene, BRCA2, was localized to a region of approximately 6 cM between D13S289 and D13S267 on chromosome 13. The report of a homozygous somatic deletion in this region in a patient with pancreatic cancer[44] narrowed the search, and finally the gene was identified by Wooster and associates[9] in December 1995.

Carriers of germline mutations in BRCA2 have an increased risk similar to that of BRCA1 carriers of developing breast cancer and a more moderately increased risk of ovarian cancer.[43] BRCA2 families also exhibit an increased incidence of male breast, pancreatic, prostate, laryngeal, and ocular cancers.[9,20]

BRCA2 is a large gene consisting 27 exons distributed over 70kb, encoding a protein of 3418 amino acids. Neither the gene nor the protein exhibits strong sequence homology with sequences on the publicly available DNA and protein sequence databases. Both BRCA1 and BRCA2 have large exons 11 (3426 and 4932 base pairs, respectively) and translational start sites in exon 2, and both code large negatively charged proteins that are highly expressed in the testis.[45]

Mutations in BRCA2 are distributed throughout the coding region, with an excess of insertions and deletions relative to BRCA1.[46] Phelan and coworkers[20] screened for BRCA2 mutations in 49 site-specific breast cancer families with 3 or more cases of breast cancer and an absence of ovarian cancer. They identified mutations in 8 families, including all 4 families with male breast cancer, and concluded that BRCA2 may be responsible for a smaller proportion of breast cancer families than was initially suggested from linkage data. The group suggested that an unidentified gene or genes may be responsible for the subset of families without BRCA1 or BRCA2 mutations.

The finding of Phelan and coworkers[20] that BRCA2 carriers are at increased risk for pancreatic cancer was given further support by the finding of a BRCA2 mutation in a pancreatic cancer cell line.[47] Additionally, the role of BRCA2 in male breast cancer was confirmed by Couch and associates,[21] who identified inactivating mutations in 7 of 50 men (14%) with breast cancer; all but 1 of the carriers had a family history of male or female breast cancer.

The 185delAG BRCA1 mutation is seen in approximately 20% of Ashkenazi Jewish women with breast cancer diagnosed under 42 years of age, and the carrier frequency is 1% in the Ashkenazi population.[22,48,49] Study of this ethnic group for BRCA2 mutations revealed a mutation in exon 11, 6174delT, that appears to be present with approximately the same frequency in the Ashkenazi population as 185delAG.[9,50] In a population-based study of approximately 3000 Ashkenazi Jewish individuals, the carrier frequency was found to be 1.09% for the 185delAG BRCA1 mutation, 0.13% for the 5382insC BRCA1 mutation, and 1.52% for the 6174delT BRCA2 mutation.[51] Knowledge of the carrier frequency of specific mutations in this population will greatly influence the counseling of Ashkenazi women regarding breast cancer risk and genetic testing, as well as the approach to mutation detection taken in the laboratory.

LOH data at 13q in sporadic breast and ovarian cancer (30%-40%) suggest that BRCA2 may also be somatically inactivated in a proportion of nonfamilial forms of these cancers.[52,53,54,55] To date, however, only a handful of somatic mutations have been described in sporadic breast and ovarian cancers.[30,47,56,57] Such studies of mutational inactivation of BRCA1 and BRCA2 in sporadic disease suggest that familial and sporadic breast and ovarian cancer may be fundamentally different diseases at a molecular genetic level.

Like BRCA1, BRCA2 mRNA expression has been shown to vary according to the cell cycle, exhibiting low levels in G0 and early G1 and maximum levels in late G1 and S phase.[58] BRCA2 mRNA expression is associated with proliferation in normal and tumor-derived breast epithelial cells.


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