BRCA1 and BRCA2 are two genes initially discovered by studying families strongly suggestive of hereditary breast cancer. Thus, they are named breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2). Several hundred mutations have been reported in BRCA1 and BRCA2 since their identification.3
The BRCA1 and BRCA2 genes are known to be involved, both separately and coor-dinately, in DNA double-strand break repair. These breaks can occur in response to ionizing radiation or DNA cross-linking agents such as cisplatin, a chemotherapeutic agent. Repair occurs through homologous recombination, by which homologous, undamaged DNA strands are invaded by a damaged single-stranded DNA. Homologous sequences are then paired, resulting in an undamaged double-stranded DNA molecule. The double-stranded break repair pathway is complex and involves numerous other genes in addition to BRCA1 and BRCA2.
BRCA genes are considered to act as tumor suppressor genes, because an inherited deleterious mutation in one allele represents the first "hit" in Knudsen's two-hit hypothesis of tumorigenesis.
If the second allele loses its function within a cell (through accumulation of damage), cancer can develop owing to the inability of the cell to repair acquired abnormalities. Precisely why BRCA1 and BRCA2 predispose specifically to breast and ovarian cancer is currently under investigation.
In light of these roles for BRCA1 and BRCA2, it is interesting to note that women with BRCA-related ovarian cancer have a better response to cisplatin-based regimens than those with sporadic ovarian cancer.4 Cisplatin generates a highly reactive species after intracellular aquation. This species binds to DNA, causing intrastrand crosslinks primarily between adjacent guanines in the DNA helix major groove. Among other cytotoxic effects, it is believed that the cisplatin-induced adducts may induce the mismatch repair (MMR) complex to produce single-strand DNA breaks, resulting in cytotoxicity and cell death.5
For genetic testing of BRCA1 and BRCA2 to be useful to families at high risk for a mutation in these genes, it is necessary to have accurate assessments of their prevalence (i.e., how common the mutations are in a particular population) and penetrance (i.e., the likelihood of mutation carriers developing cancer). Although thought to be responsible for most familial ovarian cancers,6 mutations in these two genes are generally rare. Estimations of mutation prevalence in the general population range from approximately 0.1% to 0.76% (1/1000 to 1/132).7-9 However, in women of Ashke-nazi Jewish (Eastern European) descent, approximately 2.5% (1/40) are believed to be mutation carriers.10
BRCA1 and BRCA2 mutations have a high penetrance. The lifetime risk of invasive breast cancer with a BRCA1 or BRCA2 mutation ranges from approximately 36% to 85%, depending on the study methodology.11-14 Original data were primarily based on highly selected families, such as those used for positional cloning of the genes. In these families, the estimated lifetime risk of breast cancer was over 80%; in BRCA1 carriers, the lifetime risk for ovarian cancer was between 40% and 65%, and for BRCA2 carriers, 20%.15,16 Later studies have used case-based ascertainment and, to a lesser extent, population-based data. Population-based designs to ascertain penetrance are usually performed on specific subpopulations (such as Ashkenazi Jews) known to harbor a high incidence of founder mutations to obtain an adequate number of carriers. One study of the Ashkenazim showed a 56% lifetime risk (to age 70 years) for breast cancer, and a 16% lifetime risk of ovarian cancer but did not distinguish between BRCA1 and BRCA2.10 By comparison, case-based ascertainment usually yields higher penetrance estimates, with 69% and 74% lifetime risk of breast cancer, and 54% and 23% risk of ovarian cancer in Ashkenazi Jews with mutations in BRCA1 and BRCA2, respectively.12
A meta-analysis of case-based studies showed a 65% lifetime risk for breast cancer and 39% risk for ovarian cancer in all comers with mutations in BRCA1; corresponding values for BRCA2 were 45% and 11%.14 A recent meta-analysis (including both Ashkenazi and non-Ashkenazi populations) estimated the lifetime risk of breast cancer as 55% in BRCA1 carriers and 47% in BRCA2 carriers; ovarian cancer risk was estimated as 39% in BRCA1 carriers and 17% in BRCA2 carriers.17
Penetrance estimates vary, based on the populations studied and on other risk factors such as oral contraceptive use, parity, and oophorectomy18 (Fig. 3-3). Pene-trance may also vary according to the specific location of the mutation within the gene. Analysis of BRCA1 cancer families has revealed a correlation between the mutation site and the relative risk of breast versus ovarian cancer. 3' mutations, which cause truncation of the C-terminal region, are associated with a higher proportion of breast than ovarian cancers, whereas 5' mutations, which delete a large segment of the BRCA1 protein, are associated with a mixture of breast and ovarian cancers.19 Mutations in the central region of BRCA2 (referred to as the "ovarian cancer cluster region") have been shown to be associated with a decreased risk of breast cancer relative to ovarian cancer risk20 (Fig. 3-4).
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