Approximately 5% to 10% of all breast cancer demonstrates an autosomal dominant pattern of inheritance. Hereditary breast cancer is characterized by early age at onset (5 to 15 years earlier than sporadic cases), bilaterality, vertical transmission through both maternal and paternal lines, and association with tumors of other organs, particularly the ovary and prostate gland.4,32,33 Syndromes most often associated with hereditary breast cancer are the hereditary breast ovarian cancer (HBOC) syndrome associated with mutations in the BRCA1 and BRCA2 genes, the Li-Fraumeni syndrome associated with p53 mutations, and Cowden's syndrome associated with mutations in PTEN. The clinical evidence of an autosomal dominant inherited predisposition to breast cancer was originally supported by segregation analysis, a quantitative method to determine if a particular trait is distributed in the population in a Mendelian manner of inheritance. Applied to the CASH data set, segregation analysis and goodness-of-fit tests of genetic models provided evidence for the existence of a rare autosomal dominant allele associated with increased susceptibility to breast cancer.34
In 1990, a susceptibility gene for breast cancer was mapped by genetic linkage to the long arm of chromosome 17, in the interval 17q 12-21.35 The linkage between breast cancer and genetic markers on chromosome 17q was soon confirmed by others, and evidence for the coincident transmission of both breast and ovarian cancer susceptibility in linked families was observed.4 The BRCA1 gene was subsequently identified by positional cloning methods and has been found to encode a protein of 1,863 amino acids. This susceptibility gene appears to be responsible for disease in 45%
of families with multiple cases of breast cancer only and up to 90% of families with both breast and ovarian cancer.36 A second breast cancer susceptibility gene, BRCA2, was localized through linkage studies of 15 families with multiple cases of breast cancer to the long arm of chromosome 13. Germ-line mutations in BRCA2 are thought to account for approximately 35% of multiple case breast cancer families and are also associated with male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer.37,38 The risk for breast cancer in female BRCA2 mutation carriers appears similar to that for BRCA1 carriers, but the age of onset is shifted to an older age distribution.39
Of the several hundred mutations described in these genes, most lead to a frame shift resulting in missing or nonfunctional proteins.40 In addition, tumors from individuals with BRCA1/2 mutations show deletion of the wild-type allele, supporting speculation that these genes play a role in tumor suppression. Both BRCA1 and BRCA2 also are involved in the control of meiotic and mitotic recombination and in the maintenance of genomic stability, suggesting an additional role in the DNA repair process.41-43 The growing body of data elucidating the functions of these genes suggests a gatekeeper role, characterized by interactions with other genes in the regulation of the cell cycle and DNA repair, which may provide novel opportunities to develop genotype-based therapeutic approaches to treatment and prevention. Although sporadic mutations of BRCA1/2 are rarely described, inactivation or decreased expression of these genes by epigenetic phenomena, such as hypermethylation, may account for some cases of breast and ovarian cancer in the population.44
The frequency of mutations in BRCA1 in the general population has been estimated to be 0.0006, which corresponds to a carrier frequency of 1 in 800. Carrier rates are not distributed evenly, however, and tend to concentrate in families with multiple cases of breast and/or breast/ovarian cancer. BRCA1 and BRCA2 also demonstrate differential prevalence rates in certain ethnic groups. Most notably, in the United States, three specific founder mutations, the 185delAG mutation and the 5382insC mutation on BRCA1 and the 6174delT mutation on BRCA2, have been found to be common in Ashkenazi Jews. The frequency of these three mutations approximates 1 in 40 in this population and accounts for up to 25% of early-onset breast cancer and up to 90% of families with both breast and ovarian cancer.45 Additional founder effects have been described in the Netherlands (BRCA1 2804 delAA and several large deletion mutations), in Iceland (BRCA2 995 del5), and Sweden (BRCA1 3171 ins5).46-49
The actual expression of disease in gene mutation carriers is estimated to range from 36% to 85% for breast cancer and from 16% to 60% for ovarian cancer. Male carriers of BRCA mutations are also at increased risk for breast cancer, with lifetime estimates of approximately 6%.50,51 Among female BRCA1 carriers who have already developed a primary breast cancer, estimates for a second contralateral breast cancer are as high as 64% by age 70 and for ovarian cancer as high as 44% by age 70.52 It is not generally known whether the specific location of mutations confer differential rates of penetrance, or what other genetic and/or environmental or lifestyle factors may interact with the presence of a mutation to determine expressivity. One region of BRCA2, however, the "ovarian cancer cluster region" in exon 11, appears to be associated with an increased risk of ovarian cancer and decreased risk of breast cancer.53 Ongoing studies are addressing the role of reproductive factors, endogenous and exogenous hormone exposure, diet, and lifestyle factors in the modulation of risk among carriers.
The clinical presentation of BRCA1/2-associated breast cancer indicates distinctive pathologic features. Historically, medullary, tubular, and lobular histologic findings and improved survival have been associated with familial breast cancer.54 The Breast Cancer Linkage Consortium examined histopathologic features of breast cancer in women with BRCA1/2 mutations and, when compared to controls, they showed an excess of high-grade tumors in BRCA1 carriers and a relative lack of in situ component adjacent to invasive lesions.55 High mitotic and total grade, as well as higher rates of aneuploidy, estrogen receptor (ER) negativity, and high proliferative fractions were also reported for BRCA1 carriers in kindreds followed by Henry Lynch, who also noted higher rates of medullary histology.56 The phenotype for BRCA2-related tumors appears to be more heterogeneous and may include an excess of lobular histology.57 Recently, differential gene expression profiles have been described for BRCA1, BRCA2, and sporadic breast cancers, suggesting functional differences in tumors depending on their genetic characteri-zation.58 In accordance with the poor prognostic features noted histologically for BRCA1-related breast cancer, two European studies recently reported survival rates that were similar to or worse than sporadic cases, with a significantly increased risk of contralateral breast cancer.59,60
Breast cancer is also a component of the rare Li-Fraumeni syndrome in which germ-line mutations of the p53 gene on chromosome 17p have been documented.61 First reported by Bottomley et al.,62 this syndrome is characterized by pre-menopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia and lymphoma, and adreno-cortical carcinoma. A germ-line mutation in the p53 gene has been identified in more than 50% of families exhibiting this syndrome, and inheritance is autosomal dominant with a penetrance of at least 50% by age 50. Although highly penetrant, the Li-Fraumeni gene is thought to account for less than 1% of breast cancer cases.63
One of the more than 50 cancer-related genodermatoses, Cowden's syndrome is characterized by an excess of breast cancer, gastrointestinal and gynecologic malignancies, and thyroid disease, both benign and malignant.64 Skin manifestations include multiple trichilemmomas, oral fibromas and papillomas, and acral, palmar, and plantar keratoses. Germline mutations in PTEN, a protein tyrosine phosphatase with homology to tensin, located on chromosome 10q23, are responsible for this syndrome. Loss of heterozygosity observed in a high proportion of related cancers suggests that PTEN functions as a tumor suppressor gene. Its defined enzymatic function indicates a role in maintenance of the control of cell proliferation.65 Disruption of PTEN appears to occur late in tumorigenesis and may act as a regulatory molecule of cytoskeletal function. Although it accounts for a small fraction of hereditary breast cancer, the characterization of PTEN function will provide valuable insights into signal pathways and the maintenance of normal cell physiology.66
Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neurologic deterioration, telangiec-tasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that approximately 1% of the general population may be heterozygous carriers of the mutated gene, ataxia telangiectasia-mutated (ATM), which has been localized to chromosome 11q22-23.67 The ATM gene encodes for a member of the phosphatidylinositol-3-kinase-like enzymes that are involved in cell-cycle control, meiotic recombination, telomere length monitoring, and DNA damage response pathways. AT cells are sensitive to ionizing radiation and radiomimetic drugs and lack cell-cycle regulatory properties after exposure to radiation.68 In vitro studies of AT carrier-derived lymphoblastoid cell lines have demonstrated defective control of apoptosis and mitotic spindle checkpoint control.69 Several epidemiologic studies have suggested a statistically increased risk of breast cancer among female heterozygote carriers, with estimated relative risks ranging from 3.9 to 5.1.70,71 ATM gene mutations associated with cancer in heterozygote carriers tend to be dominant negative missense mutations.72 Breast cancer among AT heterozygotes is characterized by early age at onset, bilateral disease, and prolonged survival.73 A comparative analysis of ATM transcripts in invasive breast cancers, benign lesions, and normal breast tissue found decreased expression of the ATM gene in the invasive tumors compared to the other tissues, suggesting a dominant negative effect of the mutation on breast carcinogenesis.74 Recently, two recurrent ATM mutations, T7271G and IVS10^G, were associated with an increased risk of breast cancer in multicase families in a population-based case-control study.75 Given the high heterozygote carrier rate in the population, this association could account for a significant proportion of hereditary breast cancer and poses a potential risk related to diagnostic radiation exposure in these individuals.
Breast and/or ovarian cancer may also be a feature of Peutz-Jeghers syndrome, basal cell nevus (Gorlin) syndrome, multiple endocrine neoplasia type 1 (MEN1), and HNPCC. The identification and location of these and other breast/ ovarian cancer genes will permit further investigation of the precise role they play in cancer progression and allow us to determine the percentage of total breast cancer caused by the inheritance of mutant genes. This development, in turn, will ultimately enrich our understanding of all breast and ovarian cancer, sporadic as well as hereditary, and will facilitate the identification of high-risk individuals.
Tailored management strategies for hereditary breast ovarian cancer (HBOC) are beginning to emerge. Individuals who appear to meet criteria for one of the BOC syndromes should be offered the opportunity to participate in clinical genetic counseling delivered by a team of trained healthcare professionals. Women who have tested positive for a BRCA1 or BRCA2 mutation are advised to start annual mammogra-phy between the ages of 25 and 35 years and to have clinical breast exams every 6 to 12 months.76 Because of the very early onset of breast cancer in women with germ-line p53 mutations, routine screening is recommended starting at age 20 to 25 for this group.77 There are preliminary data that magnetic resonance imaging (MRI) of the breast may be more sensitive in detecting early lesions in young women with dense breast tissue, although specificity is generally lower,78 and several trials are under way to determine the role of this imaging modality, especially in the setting of familial risk. Men testing positive for a BRCA1/2 mutation should also consider annual screening with mammography and clinical breast exam as well as annual prostate cancer screening with digital rectal exam and prostate-specific antigen (PSA) testing.76
Screening recommendations are problematic for ovarian cancer, for which no test or series of tests have been found to be sufficiently sensitive and specific. Despite the limitations, however, many practitioners have begun screening with the combination of pelvic exam, transvaginal ultrasound, and CA-125 in women with a family history of ovarian cancer. Although it is an important component of complete gynecologic care, the pelvic exam alone is clearly insufficient to detect most limited, early-stage epithelial ovarian tumors. Tumor markers, such as CA-125, lack the sensitivity and specificity to serve as the sole form of screening. Transvaginal ultrasound is currently being studied in a large screening trial nationwide and may prove to offer the best alternative to detect early-stage ovarian cancers. A recent report of the use of proteomics to identify early-stage ovarian cancer may represent a breakthrough for ovarian cancer screening. Pro-teomics is a new and emerging technology that can identify low molecular weight molecules in a high-throughput, non-biased discovery approach using patient serum, plasma, urine, or tissue specimens. Petricoin et al.79 identified a small set of key protein values from patient serum that discriminated ovarian cancer cases from unaffected controls with a sensitivity of 100% and a specificity of 95%. Ultimately, a complementary series of markers may be combined for use in conjunction with ultrasonography to improve the predictive value of the screening process.
Outcome data from chemoprevention trials are just beginning to emerge. The recently completed Breast Cancer Prevention Trial, which randomized more than 13,000 high-risk women to the antiestrogen tamoxifen or placebo found a 49% reduction in the incidence of breast cancer among women in the tamoxifen arm.80 The reduction in risk was limited to estrogen receptor-positive tumors. A very limited subset analysis of these data indicated that women with BRCA1 mutations (who are more likely to develop hormone receptor-negative breast tumors) did not benefit from tamox-ifen whereas those with BRCA2 mutations did.81 A second large trial comparing tamoxifen to the selective estrogen receptor modulator raloxifene is under way.
To date, there have been no Phase III randomized chemo-prevention trials for ovarian cancer. However, because of the strong epidemiologic association between oral contraceptive (OC) use and a reduction in ovarian cancer rates,82 many gynecologists are recommending their use in women with an increased risk from either family history or nulliparity. Preliminary data from studies of women with BRCA1/2 mutations suggest that they enjoy the same degree of protection (approximately 40% reduction) from OCs as do women in the general population. Small pilot studies are now under way to determine the chemopreventive role of other agents, including members of the retinoid family as well as progestational agents.
Prophylactic oophorectomy is being considered by women with a family history of ovarian cancer, particularly those who are BRCA1/2 mutation carriers, because of the uncertain nature of screening and the high case-fatality rate of advanced-stage cancer. Two large recent studies demonstrated an 85% to 96% reduction in ovarian cancer and a 50% reduction in breast cancer among women undergoing oophorectomy for prophylaxis.83,84 Prophylactic surgery does not, however, eliminate the risk for primary peritoneal cancer, which is estimated to range from 1.9% to 10.7%.85 Furthermore, premenopausal women choosing this option must consider the long-term consequences of surgically induced menopause. Similarly, prophylactic mastectomy does not completely eliminate the risk of subsequent breast cancer, although a recent retrospective review of 2,029 women who had elected the procedure for a variety of reasons estimates a greater than 90% reduction in risk.86 This finding was supported by a prospective study of BRCA1/2 carriers in which no breast cancers were observed in the 76 women who underwent prophylactic mastectomy.87 This consideration occurs most commonly among women from high-risk families or those with known BRCA1/2 mutations who are making treatment choices for their first primary breast cancer, given the increased rate of second cancers in the same breast as well as the contralateral breast in that setting. Another indication for the procedure among high-risk women is extremely dense breast tissue, which renders both clinical breast examination and standard mammography less reliable. Studies are now under way to prospectively follow women who elect prophylactic oophorectomy or mastectomy to monitor long-term disease reduction as well as to document the variables influencing the decision to pursue prophylactic surgery and the medical and psychologic consequences of the surgery.
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