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CANCER & TREATMENTS SUPPORT & SURVIVORSHIP PREVENTION & RISK ASSESSMENT CLINICAL TRIALS & RESEARCH | |
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Home > Prevention & Risk Assessment > Genetics > Breast and Ovarian Cancer Genetic Risks Breast Cancer Genetics and Clinical PracticeA woman's lifetime risk for developing breast cancer is estimated to be one in eight (12.5%), with approximately 185,000 women diagnosed with breast cancer each year (1). Research into familial breast and ovarian cancer has so far led to the identification of two main breast cancer susceptibility genes, BRCA1 and BRCA2. Other genes, such as TP53, PTEN and ATM, also are known to be involved in causing hereditary breast cancer. Families with inherited mutations in BRCA1 or BRCA2 are likely to have an apparent excess of cases of early onset breast and/or ovarian cancer that follow an autosomal dominant pattern of inheritance. It is estimated that one out of 300 individuals in the general population carries a BRCA1 or BRCA2 mutation, one out of 40 Ashkenazi Jews carries a BRCA1 or BRCA2 mutation, and one out of 2,500 Ashkenazi Jews carries two mutations. Located on chromosome 17q21, BRCA1 is a tumor suppressor gene that appears to be involved in the double-stranded DNA error correction function. Current risk estimates for BRCA1 mutation carriers is a 55 to 85% lifetime risk for breast cancer and a 20 to 40% lifetime risk for ovarian cancer. Men who inherit a BRCA1 mutation have a theorectical elevated lifetime risk for male breast cancer and a mildly elevated lifetime risk of prostate cancer. Both men and women BRCA1 mutation carriers may also have an elevated lifetime risk for colon cancer. BRCA2, located on chromosome 13q12, is also a tumor suppressor gene, BRCA2 mutations appear to confer a similar female breast cancer risk to that seen with BRCA1 mutations. However, the risk of ovarian cancer for BRCA2 mutation carriers appears to be lower, with up to a 27% lifetime risk for developing ovarian cancer (2). Male breast cancer, a rare disease in the general population, is much more common in the BRCA2 families. Male BRCA2 mutation carriers have up to a 6% lifetime risk for developing breast cancer (3). Detailed pedigree analyses of BRCA2 families have identified other malignancies that include: laryngeal, prostate, pancreatic and gastrointestinal cancers, which may occur with increased frequency compared to that of the general population (4). DNA sequencing is the most sensitive for BRCA1 and BRCA2 mutation detection, as it determines the nucleotide sequence of the coding regions of genes. It is estimated that sequencing will uncover nearly 85-90% of all the mutations in the coding regions of BRCA1 and BRCA2, but will consistently miss mutations in non-coding regions of genes and large genomic deletions. This phenomenon is evident, for example, in the Dutch population, where 20 to 30% of individuals with a strong family history of breast cancer will have a negative BRCA1 and BRCA2 sequencing result. Genomic deletion testing is available for families with a negative BRCA1 and BRCA2 sequencing result who meet certain criteria. A test known as the "multi-site 3 BRCAnalysis" tests for three specific mutations (187 delAG, 5385insC and 6174delT) found in BRCA1 and BRCA2 that are common among people of Ashkenazi Jewish descent. Since 1/2500 individuals of Ashkenazi Jewish ethnicity will carry two of these "founder" mutations, it is recommended that all Ashkenazi Jewish individuals seeking BRCA1 and BRCA2 mutation testing receive testing for all three founder mutations, even if a particular mutation is already known in the family. A mutation-specific test is used when a mutation has been identified in an affected family member. This test looks only for the one specific mutation previously identified in the family. If the test result is negative, the risk for breast cancer in that individual is not zero, but usually equivalent to that of the general population. It is important that the full family cancer history of both the paternal and maternal lineages be known in detail before ordering this test for a second or higher degree relative of a mutation carrier, as additional types of tests may be indicated as well. The outcomes of a genetic test for a cancer susceptibility gene need to be interpreted in the context of the known mutations and the individual's specific history. A positive test result means that a known deleterious mutation has been found, which correlates with an increased risk for developing cancer. An inconclusive test result means that a mutation is found, but it is unknown whether the mutation correlates with an increase risk for developing cancer. This inconclusive test result is called a variant of uncertain significance. Information on these variants is available through a worldwide web-based databank, the Breast Information Core (BIC). As more information is gathered, these variants can be reclassified to known deleterious mutations or polymorphisms. A negative test result means that no mutation was found in the coding region of BRCA1 and BRCA2. However, it is possible that there is a mutation in areas of BRCA1 and BRCA2 that cannot be identified using current methods, along with the possibility the cancers in the family may be associated with a mutation in an uncharacterized cancer susceptibility gene. Finally, regardless of a family's mutation status, it is possible that some of the cancers seen in the family are sporadic or due to other causes. Because their risk for developing breast cancer is increased over that of the general population, tamoxifen and raloxifene have been offered as a chemopreventive option for BRCA1 and BRCA2 mutation carriers, to aid in reducing their risk for developing breast cancer. Although the exact risk reduction of these medicines is not know in this patient population, it is thought to reduce the risk of developing breast cancer by about 45%. Other prevention options available to BRCA1 and/or BRCA2 mutation carriers are prophylactic bilateral mastectomy and prophylactic bilateral salpingo oophorectomy. Prophylactic bilateral mastectomy reduces the risk of breast cancer by 90% in this patient population. Prophylactic bilateral salpingo oophorectomy significantly reduces the risk of ovarian cancer by 90-95%. Researchers have shown that the failure rate of prophylactic bilateral salpingo oophorectomy is between 2% and 11% (6) (7). The resulting cancer is peritoneal carcinomatosis. It is unknown at this time whether the risks of peritoneal carcinomatosis are increased for BRCA1 and BRCA2 mutation carriers. Genetic testing and cancer risk management is a complex and dynamic process. Even with our current ability to sequence genes and study complex models of genetic abnormalities, the science of genetic testing has limitations that must be adapted to clinical applications. It should be noted that in some high-risk women, drastic surgical measures do not always assuage all cancer fears. Therefore, consistent protocols for counseling must be in place to help manage cancer risk evaluation patients. References
For more information, please contact Cancer AnswerLine 800-865-1125 or visit their web page. written by: revised 12/2006 |
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See also:
Family Matters: When Cancer is Inherited This article provides information on genetic counseling
University of Michigan Comprehensive Cancer Center This site is part of the U-M Health System. The information presented is not a tool for self diagnosis or a substitute for professional care. © 2008 U-M Comprehensive Cancer Center |
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