Genes and Breast Cancer
Genes and Breast Cancer
Basic Science UpdateSynopsis: At least eight candidate breast cancer susceptibility genes have been identified. Tests are in development to identify women at increased risk. However, in the absence of an effective noninvasive prevention strategy, women at high-risk are faced with a difficult choice, whether or not to undergo prophylactic bilateral mastectomy, and in some cases, oophorectomy.
Source: Greene MH. Mayo Clin Proc 1997;72:54-65.
Familial breast cancer is generally diagnosed when the patient is young, is more frequently bilateral, and may be associated with an increased risk of other neoplasms.About 45% of families with site-specific breast cancer have a mutation in BRCA-1, a gene that maps to chromosome 17q21. The cumulative breast cancer risk among women carrying a mutant BRCA-1 is 51% at age 50 years and 85% at age 70. The risk of ovarian cancer is 29% by age 50 years and 44% by age 70. In addition, colon cancer is said to occur four times more frequently among people with BRCA-1 mutations than among the general population. Prostate cancer may be three-fold more common. Male breast cancer is not part of BRCA-1-associated disease spectrum. Early work examining the mutations in BRCA-1 has documented that many different sites in the gene may be mutated. Interestingly, the most common mutation, a deletion of an adenine and guanine dinucleotide at position 185 (so called 185delAG) accounts for about 12% of the mutations and is disproportionately expressed in Ashkenazi Jewish families. Thus, while BRCA-1 mutations probably account for not more than 5% of all breast cancer, they may be responsible for up to 16% of all breast cancer and 39% of ovarian cancer in Ashkenazi women under the age of 50.
BRCA-2 maps to chromosome 13q12-13, is associated with both breast and ovarian cancer, though less ovarian cancer than seen with BRCA-1 mutations, and an increased risk of male breast cancer. Pancreatic, prostate, and colon cancer may also be increased in families carrying BRCA-1 mutations. BRCA-2 mutations may account for 3% of breast cancer overall. As was seen for BRCA-1 mutations, a particular BRCA-2 mutation is overrepresented in Ashkenazi Jews, 6174delT. In a group of Ashkenazi Jewish women in New York diagnosed with breast cancer, 6174delT was identified in 8%, about one-fourth the rate of the 185delAG mutation in BRCA-1 in these same women. However, the incidence of the two mutations in the Ashkenazi Jewish population as a whole is the same, about 1%. This implies that BRCA-1 mutations are more likely to produce breast cancer than BRCA-2 mutations. BRCA-2 accounts for most familial breast cancer in Iceland and is associated with a particular mutation, 999del5.
About 10-20% of families at high risk for breast cancer have no linkage to either BRCA-1 or BRCA-2. Linkage analysis has suggested that a third gene (BRCA-3?) might map to chromosome 8p12-22. None of the families with this linkage showed an increased risk of ovarian cancer. However, since a gene has not yet been cloned, it has not been possible to identify the syndrome associated with mutations.
Breast cancer is one of the tumors that occurs with increased frequency in the Li-Fraumeni syndrome, associated with germline mutations in the p53 gene on chromosome 17p13.1. Sarcomas, brain tumors, adrenal tumors, and leukemias are also found in Li-Fraumeni families. About 50% of women with germline p53 mutations develop breast cancer by age 50; p53 mutations are not commonly found in sporadic breast cancers, thus, p53 appears to contribute to the pathogenesis of breast cancer only in the specific setting of Li-Fraumeni syndrome.
Cowden’s disease is a rare autosomal dominant disorder characterized by papillomatosis of the lips and oropharynx, high arched palate, jaw hypoplasia, thyroid adenomas and cancers, central nervous system anomalies, and breast cancer. About 30% of women affected with Cowden’s disease develop breast cancer, often bilaterally, before age 50. The gene for Cowden’s disease has not been cloned but it maps to chromosome 10q22-23.
Two families have been described in which multiple male breast cancers were associated with germline mutations in the androgen receptor on chromosome Xq11.2-12.
Ataxia telangiectasia is an autosomal recessive disorder associated with progressive neurologic dysfunction (ataxia, chorea, oculomotor abnormalities), telangiectasias of the skin and eyes, immunodeficiency, sensitivity to ionizing radiation, and an increased incidence of lymphoma. Analysis of female relatives of patients with ataxia telangiectasia who are heterozygous for the mutated AT allele on chromosome 11q22-23 reveals a nearly four-fold increased risk of breast cancer. The true prevalence of mutations in the AT gene in the general population is not clear, but has been estimated to be as high as 1%. If the gene mutations are that prevalent, AT could be associated with as much as 8% of breast cancer occurring in patients less than 40 years old.
The Harvey-ras or H-ras proto-oncogene maps to chromosome 11p15.5. One kilobase downstream of H-ras is a region that consists of a variable number of tandem repeats of a 28 base pair fragment of H-ras. The size of this segment is variable and is controlled in allelic form. Some authors have suggested that certain rare alleles are associated with a two-fold increased risk of breast cancer. This makes little or no sense. However, recently another gene that maps to the same region, called tsg101 (tumor suppressor gene 101), has been found to be mutated in seven of 15 uncultured primary human breast carcinomas.1 It is not yet clear how this gene works, or if mutations in the germline gene are compatible with life. However, it is possible that this newly identified gene plays a large role in sporadic breast cancers and at least a small role in familial breast cancers.
BRCA-1 and BRCA-2 are clearly the most important genes in familial breast cancer. Tests to identify mutations in these genes are being developed. When these tests are readily available, what should be our approach to using them? This question has been highly contentious. However, we still lack a significant amount of understanding of what the presence of mutations actually means. Most of the figures are projected on the basis of a small number of families each with six or more clinically affected members. What should we advise patients based upon the results? How can we be sure that differences detected in such tests are true mutations rather than normal allelic variants? More information is required before we can answer these and the many other questions raised by the potential for genetic testing. The recent position paper published by the American Society of Clinical Oncology addresses some of the problems in detail.2
References
1. Li L, et al. Cell 1997;88:143-154.2. American Society of Clinical Oncology. J Clin Oncol 1996;14:1730-1736.
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