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Please note: This article is part of the Cancer Center's News Archive and is here for historical purposes. The information and links may no longer be up-to-date.

Michigan Oncology Journal Spring 2000

Breast Cancer Genetics and Clinical Practice

Kara J. Milliron, M.S.,
Genetic Counselor

Sofia D. Merajver, M.D., Ph.D.
Associate Professor of Internal Medicine
Director, Breast and Ovarian Cancer Risk Evaluation Program

A 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 Ashkenazic Jews carries a BRCA1 or BRCA2 mutation, and one out of 2,500 Ashkenazic 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. Mutations in BRCA1 are responsible for approximately 50% of all inherited predisposition to breast cancer. Current risk estimates for BRCA1 mutation is 55 to 85% lifetime risk for breast cancer and 20 to 40% lifetime risk for ovarian cancer. Men who inherit a BRCA1 mutation have a mildly elevated lifetime risk for prostate cancer. BRCA1 mutation carriers may also have an elevated lifetime risk for colon cancer.

BRCA2, located on chromosome 13q12, is also a tumor suppressor gene, but little is known about its actual function. Mutations in BRCA2 account for approximately 35% of the remaining hereditary breast cancers. 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 98% 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.

A test known as "The Ashkenazic Jewish panel" or the "multi-site 3 BRCAnalysis" tests for three specific mutations (185 delAG, 5382insC and 6174delT) found in BRCA1 and BRCA2 that are common among people of Ashkenazic Jewish descent. Since 1/2500 individuals of Ashkenazic Jewish ethnicity will carry two of these "founder" mutations, it is recommended that all Ashkenazic 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 has been offered as a chemopreventive option for BRCA1 and BRCA2 mutation carriers. However, as of this writing, the effect of tamoxifen as a chemoprevention agent in BRCA mutation carriers is not completely known. Studies are currently investigating the BRCA mutation status of many participants from the original breast cancer prevention trial. The expectation is that when the data are analyzed, the results will prove efficacy.

One prevention option available to BRCA1 and/or BRCA2 mutation carriers is prophylactic bilateral mastectomy. Researchers from the Mayo Clinic published findings that prophylactic mastectomy was associated with a reduction in breast cancer incidence by approximately 90%, in women designated at high risk for developing breast cancer (5). However, it is not known how many of these women actually had a BRCA1 and/or BRCA2 mutation. The inclusion criteria used to define their "high-risk" women are very broad and include variables that may not be associated with mutations in BRCA1 and BRCA2.

Prophylactic bilateral oophorectomy is considered a prevention option for women at high risk for developing ovarian cancer. This procedure significantly reduces the risk of ovarian cancer, but does not completely eliminate the risk. Researchers have shown that the failure rate of prophylactic bilateral 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. It is reasonable to screen for peritoneal carcinomatosis by CA-125 blood tests.

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.


  1. Brody L, Biesecker B. Breast cancer susceptibility genes: BRCA1 and BRCA2. Medicine 1998; 77(3):208-226.
  2. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 1994; 343:692-695.
  3. Easton DF, Steele L, Fields P, Ormistin W, Averill D, Daly PA. Cancer risk in two large breast cancer families linked to BRCA2 on chromosome 13q12-13. Am J Hum Genet 1997; 61:120-128.
  4. Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. JNCI 1999; 91:1310-1316.
  5. Hartman L, Schaid D, Woods J, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Eng J Med 1998; 340:77-84.
  6. Piver MS, Jishi MF, Tsukada Y. Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer. Cancer 1993; 71:2751-2755.
  7. Tobacman JK, Tucker MA, Kase R. Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian cancer prone families. Lancet 1982; 795-797.

Breast and Ovarian Cancer Risk Evaluation Clinic
The Breast and Ovarian Cancer Risk Evaluation Program at the University of Michigan Compre hensive Cancer Center provides individuals with an accurate assessment of their personal risk for developing breast and other related cancers, and offers a comprehensive plan for follow-up and preventative care.
The program offers:

  • review of family history, highlighting cancer occurrence
  • education in basic genetic principles as applied to breast and ovarian cancer o discussion of individualized risk (based on family history and personal risk factors)
  • instruction in proper breast self-examination technique
  • discussion of behaviors thought to effect the risk of various cancers
  • education regarding genetic testing and availability of research protocols
  • presentation of an individualized plan for follow-up care
  • recommendations with respect to lifestyle issues and choices
  • written summary of the visit sent to your referring physician
  • confidential patient summary letter that reviews the genetic counseling session


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Please note: The articles listed in the Cancer Center's News Archive are here for historical purposes. The information and links may no longer be up-to-date.
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