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Breast and Ovarian Cancer
  The Testing Process in the Ashkenazi Jewish Population

By Kathleen Fergus, MS, CGC and Jill Simonsen

Reviewed by Beth Crawford, MS, CGC and Miriam Komaromy, MD


 

Genetic testing can be like looking for a needle in a haystack, especially in the case of breast and ovarian cancer, where scientists are dealing with two extremely large genes (BRCA1 and BRCA2) and hundreds of possible mutations. However, for people of Ashkenazi Jewish descent genetic testing is somewhat simplified. This is because scientists know that 90 percent of the time, an Ashkeanzi Jewish family with a pattern of hereditary breast and ovarian cancer will have one of three specific mutations. This has made it possible to develop a test that looks only for the presence or absence of these three specific mutations, rather than the hundreds that can be associated with these types of cancer in other populations.

 
 
 

The Test

Three specific mutations in the BRCA1 and BRCA2 genes account for most of the cases of hereditary breat and/or ovarian cancer in the Ashkenazi Jewish population.
The test, called multisite analysis, looks exclusively for the three mutations in the BRCA1 and BRCA2 genes (185delAG* and 5382insC* in BRCA1, and 6174delT in BRCA2) that are thought to account for the majority of inherited breast and ovarian cancer in people of Ashkenazi Jewish descent. If there is a mutation that is responsible for the cancer in an Ashkenazi Jewish family, approximately 90 percent of the time it will be one of these three mutations. Because this type of test only examines the precise locations on the BRCA1 and BRCA2 genes where these three mutations are known to occur, it is quick and inexpensive compared to DNA sequencing, which examines a much larger region of both genes.

Multisite analysis is only recommended for people of Ashkenazi Jewish descent because it only detects the three mutations that have been linked to breast and ovarian cancer in Ashkenazi Jewish families. For other populations, this test would narrow the search for mutations in BRCA1 and BRCA2 prematurely because there are hundreds of mutations that could be associated with their breast and/or ovarian cancer history.

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Interpreting the Results

Multisite testing will yield either a positive result or a negative result, which can be interpreted as follows:

  • Positive. If multisite analysis reveals one of the mutations it's designed to detect, this is referred to as a positive result. The person being tested has inherited one of the three mutations known to be associated with hereditary breast and ovarian cancer in individuals of Ashkenazi Jewish descent and is thus at increased risk for these diseases.

  • Negative. If multisite analysis fails to reveal one of the three mutations it's designed to detect, this is referred to as a negative result. However it does not rule out the less likely possibility that this person could have a mutation somewhere else on the BRCA1 or BRCA2 gene. (Remember: these three mutations only account for approximately 90 percent of all hereditary breast and ovarian cancer in the Ashkenazi Jewish population.)

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Limitations of Multisite Analysis

A negative test result does NOT mean that you are free of a mutation or increased cancer risk. It only means that you don't have one of three specific mutations.
Although multisite analysis detects the three mutations that account for the majority of inherited breast and ovarian cancers in people of Ashkenazi Jewish descent, it does not detect any of the hundreds of other mutations that have been associated with these types of hereditary cancer in the broader population. This means that a woman who tests negative via multisite analysis cannot absolutely assume she's free of a mutation or the increased cancer risk a mutation would confer. She simply knows that she doesn't have one of the mutations that are most likely to be associated with these types of cancer in people of similar ancestry. For this reason, some individuals who test negative for a mutation in this type of test opt to undergo more comprehensive DNA sequencing.

Multisite Testing One Family's Experience

Multisite Testing One Family's Experience Marion is a 45-year-old woman of Ashkenazi Jewish descent who was diagnosed with breast cancer a year ago and is currently undergoing treatment with chemotherapy. Marion has two daughters, ages 11 and 13. Although Marion is eager to know whether there's a genetic basis for her cancer, she's worried about getting an ambiguous result that will only increase her anxiety about her daughters' risk. Marion's mother is alive, well, and cancer-free at age 68. However, her father was diagnosed with prostate cancer at age 71, though he, too, is currently alive and doing well. His sister, Marion's paternal aunt, was diagnosed with breast cancer at age 67 and died two years later of metastatic breast cancer. Marion has numerous other aunts, uncles, and cousins, all of whom are in good health and cancer-free.

The Decision

Because her personal history and ethnicity make one of the three BRCA1 or BRCA2 mutations detected in Ashkenazi Jewish women the most likely genetic culprit for her cancer, Marion discusses her options with her doctor and a genetic counselor and decides to pursue testing via multisite analysis. An additional benefit to this testing approach is that there is no chance of getting an ambiguous result. Marion will either have one of these mutations or she won't.

  • If Marion tests positive for a mutation, she'll have an explanation for her family's cancer and can alert other adult relatives of their increased risk as well as their options for testing. She will also know that her daughters have a 50 percent chance of inheriting the altered gene and the cancer risk that goes with it. If, on the other hand, Marion tests negative, she will know that she hasn't inherited one of the three mutations.

The Result

Marion tests negative for the mutations. Although she realizes that a negative result does not explain her breast cancer or lower her risk for other cancers, she's glad she decided to have multisite analysis. Her test result reduces the likelihood that there is a BRCA mutation in her family, but does not entirely rule it out.

Since she was only interested in finding out whether she had one of the mutations most commonly associated with individuals of Ashkenazi Jewish descent, she now feels that she has closure regarding her family history and has decided not to pursue other testing at this time. Marion will need to discuss with her genetic counselor and doctor whether or not to pursue ovarian cancer screening, now that she has tested negative.


Notes: *A recent change in numbering of the individual bases of the BRCA1 and BRCA2 genes has resulted in a change in the naming of certain mutations; thus the mutations commonly referred to as 185delAG and 5382insC should technically be referred to as 187delAG and 5385insC, respectively.

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References

Beller, U. D. et al. (1997). High frequency of BRCA1 and BRCA2 germline mutations in Ashkenazi Jewish ovarian cancer patients, regardless of family history [see comments]. Gynecol Oncol 67(2): 123-6.

Biesecker, B. B. and Brody, L.C. (1997). Genetic susceptibility testing for breast and ovarian cancer: a progress report. J Am Med Womens Assoc 52(1): 22-7.

Myriad (2000). Multisite analysis of three founder mutations in Ashkenazi population accounts for 90% of inherited mutations in this population. K.Fergus. San Francisco, Myriad.

Phillips, K. A. et al. (2000). Perceptions of Ashkenazi Jewish breast cancer patients on genetic testing for mutations in BRCA1 and BRCA2. Clin Genet 57(5): 376-83.

Roa, B.B. et al. (1996). Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet. 14:188-90.

Shattuck-Eidens, D. et al. (1997). BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA 278(15): 1242-50.

Strewing, J.P. et al (1995) The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 11:198-200.

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