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MedicineWorld.Org: BRCA1 and BRCA2 : Breast cancer associated genes

BRCA1 and BRCA2 : Breast cancer associated genes   

         By Kottapurath Kunjumoideen MD
        BRCA2 mutations with women who do not have such mutations. Therefore, the percentages given above are estimates that may change as more data become available.

      Since BRCA1 and BRCA2 mutations may also be associated with increased risk of development of breast cancer at younger age, hence when a young woman develops breast cancer this possibility should be explored especially with other family members affected with breast or ovarian cancer. Both BRCA1 and BRCA2 are inherited as autosomal dominant mode and can be passed to offspring by either paternal or maternal lineage.

      In the general population the incidence of BRCA1 mutation is between 1 in 500 and 1 in 800. The incidence of BRCA2 mutation is even lower. Individuals with Ashkenazi Jewish background have an increased incidence of BRCA1 and BRCA2 mutations. 1 in 40 of individuals with Ashkenazi Jewish background may be affected with BRCA1 or BRCA2 mutation. The most common mutation in BRCA1 is called 185delAG.

      BRCA1 associated breast cancer tend to be high-grade and hormone receptor negative, however it is not clear if the overall out come is different from breast cancer not associated with BRCA mutations. BRCA2 associated breast cancer tends to resemble the regular mutation unrelated breast cancer.

      BRCA1 and BRCA2 are not the only genetic abnormalities that increase risk of breast cancer. Mutations in several other genes, including TP53, PTEN, STK11/LKB1, CDH1, CHEK2, ATM, MLH1, and MSH2, have been associated with hereditary breast and or ovarian tumors (Ref 5-6). These mutations account for only a minor fraction of hereditary breast cancers. The great majority of hereditary breast cancer occurs in carriers of BRCA1 and BRCA2. Overall, it has been estimated that inherited BRCA1 and BRCA2 mutations account for 5 to 10 percent of the total breast cancers and 10 to 15 percent of the total ovarian cancers among white women in the United States (Ref 7).

      Different groups of people may have mutations in different places of BRCA1 and BRCA2 genes. In other words, BRCA1 mutation in one family may be different form another family harboring BRCA1 mutation. For example, three specific mutations, two in the BRCA1 gene and one in the BRCA2 gene, are the most common mutations found in these genes in the Ashkenazi Jewish population. In one study, 2.3 percent of participants (120 out of 5,318) carried one of these three mutations (Ref 8). This frequency is about five times higher than that found in the general population. It is not known whether the increased frequency of these mutations is responsible for the increased risk of breast cancer in Jewish populations compared with non-Jewish populations.

      Other ethnic and geographic populations around the world, such as the Norwegian, Dutch, and Icelandic peoples, also have higher frequencies of specific BRCA1 and BRCA2 mutations.

      In addition, limited data indicate that the frequencies of specific BRCA1 and BRCA2 mutations may vary among individual racial and ethnic groups in the United States, including African Americans, Hispanics, Asian Americans, and non-Hispanic whites (Ref 9, 10, 11).

      There are several methods are available to test for BRCA1 and BRCA2 mutations (Ref 12). Most of these methods look for changes in BRCA1 and BRCA2 DNA. At least one method looks for changes in the proteins produced by these genes. Frequently, a combination of methods is used.

      Testing is simple on the part of the patient. Only a blood sample is needed for these tests. It usually takes several weeks or longer to get the test results. Genetic counseling is generally recommended before and after a genetic test. This helps to choose the right person for the test and to make the person aware of the ethical consequences of BRCA gene testing and to cope with the psychological and social stress involved with the BRCA testing. This counseling is usually performed by should be performed by a health care professional who is experienced in cancer genetics.

      BRCA testing involves minimal medical risk, however the fact that the test result can have significant effect on a person’s emotions, social relationships, finances, and medical choices should not be ignored.

      People who receive a positive test result may feel anxious, depressed, or angry. They may choose to undergo preventive measures, such as prophylactic surgery, that have serious long-term implications and whose effectiveness is uncertain.

      People who receive a negative test result may experience “survivor guilt,” caused by the knowledge that they likely do not have an increased risk of developing a disease that affects one or more loved ones.

      Because genetic testing can reveal information about more than one family member, the emotions caused by test results can create tension within families. Test results can also affect personal choices, such as marriage and childbearing. Issues surrounding the privacy and confidentiality of genetic test results are additional potential risks.

      Once the test is performed the results of the test is normally included in a person’s medical records. Consequently, individuals considering genetic testing must understand that their results might not be kept private. This information however is covered by Privacy Rule of the Health Information Portability and Accountability Act (HIPAA) of 1996 (Ref 13). The Privacy Rule requires that health care providers and others protect the privacy of health information, sets boundaries on the use and release of health records, and empowers individuals to control certain uses and disclosures of their health-related information. Many states also have laws to protect the privacy and limit the release of genetic and other health information.

        In 2008, the Genetic Information Nondiscrimination Act (GINA) became Federal law. GINA prohibits discrimination based on genetic information in relation to health insurance and employment, but the law does not cover life insurance, disability insurance, and long-term care insurance (Ref 14, 15). When applying for these types of insurance, people may be asked to sign forms that give an insurance company permission to access their medical records. The insurance company may take genetic test results into account when making decisions about coverage.

      Some physicians keep genetic test results out of medical records. However, even if such results are not included in a person’s medical records, information about a person’s genetic profile can sometimes be gathered from that person’s family medical history.

      In 1990 BRCA1 was localized to chromosome 17 and the gene was cloned in 1994. Mutations in BRCA1 gene are associated with 50 percent to 85 percent life-time risk of developing breast cancer as seen in various studies. Carriers of BRCA1 gene mutation often develop breast cancer at a younger age compared to the general population. The risk of developing ovarian cancer is also elevated in carriers of BRCA1 mutation, but not to the level of increase in breast cancer risk. If a family has relatives with early onset breast cancer and ovarian cancer, the possibility of BRCA mutation should always be considered. Men with BRCA1 mutation generally do not have an increase risk of development of breast cancer, and this is in contrast to BRCA2 mutation which causes increased risk of breast cancer development in the male carriers as well. BRCA1 mutations carriers may have increased of developing cervical, uterine cancer. BRCA1 carriers including men may have increased risk of pancreatic, and colon cancer. Men carrying BRCA1 mutation may have increased risk of prostate cancer. (Ref 2, 3).

      BRCA2 gene is located on chromosome 13. The risk of development of breast cancer in women carrying BRCA2 mutations are BRCA2 gene is located on chromosome 13. The risk of development of breast cancer in women carrying BRCA2 mutations are similar to the risk of BRCA1 carriers, however the risk of development of ovarian cancer is lower in BRCA2 mutation carriers compared to BRCA1 mutation carriers. Men carrying BRCA2 mutation have an increased risk of developing breast cancer and the lifetime risk for a male carrier is about 5 percent. Breast cancer in a male is rare, but when it occurs it may be associated with BRCA2 mutation. BRCA2 mutations may also increase risk of other cancer including pancreatic cancer, stomach cancer, gallbladder and bile duct cancer, and melanoma (Ref 4).

  1. National Cancer Institute. SEER Cancer Statistics Review, 1975–2005
  2. Thompson D, Easton DF, the Breast Cancer Linkage Consortium. Cancer incidence in BRCA1 mutation carriers. Journal of the National Cancer Institute 2002; 94(18):1358–1365.
  3. The Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. Journal of the National Cancer Institute 1999; 91(15):1310–1316.
  4. Campeau PM, Foulkes WD, Tischkowitz MD. Hereditary breast cancer: New genetic developments, new therapeutic avenues. Human Genetics 2008; 124(1):31–42.
  5. PDQ® Cancer Information Summary. National Cancer Institute; Bethesda, MD. Genetics of Breast and Ovarian Cancer (PDQ®)
  6. Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. Journal of the American Medical Association 2006; 295(12):1379–1388.
  7. Lynch HT, Silva E, Snyder C, Lynch JF. Hereditary breast cancer: Part I. Diagnosing hereditary breast cancer syndromes. The Breast Journal 2008; 14(1):3–13.
  8. Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. New England Journal of Medicine 1997; 336(20):1401–1408.
  9. John EM, Miron A, Gong G, et al. Prevalence of pathogenic BRCA1 mutation carriers in 5 U.S. racial/ethnic groups. Journal of the American Medical Association 2007; 298(24):2869–2876.
  10. Vogel KJ, Atchley DP, Erlichman J, et al. BRCA1 and BRCA2 genetic testing in Hispanic patients: Mutation prevalence and evaluation of the BRCAPRO risk assessment model. Journal of Clinical Oncology 2007; 25(29):4635–4641.
  11. Malone KE, Daling JR, Doody DR, et al. Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Research 2006; 66(16):8297–8308.
  12. Palma M, Ristori E, Ricevuto E, Giannini G, Gulino A. BRCA1 and BRCA2: The genetic testing and the current management options for mutation carriers. Critical Reviews in Oncology/Hematology 2006; 57(1):1–23.
  13. U.S. Department of Health and Human Services. HIPAA
  14. H.R. 493. The Genetic Information Nondiscrimination Act of 2008
  15. The National Human Genome Research Institute. GINA: The Genetic Information Nondiscrimination Act of 2008


BRCA1 and BRCA2 : Breast cancer associated genes

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