For people in families who have a pattern of hereditary breast and/or ovarian cancer, but who have not had genetic testing yet, DNA sequencing is the best place to begin.
If DNA sequencing reveals the genetic culprit for a family's hereditary breast and ovarian cancer, other at-risk family members can then be tested for the same mutation. And they can do so with a cheaper and less time-consuming test called single site analysis.
The DNA Sequencing Test
Interpreting the Results
Advantages and Limitations of Sequencing
The DNA Sequencing Test
This test looks at the DNA of two genes — BRCA1 and BRCA2 — that are known to have changes that can cause breast or ovarian cancer. The test looks for thousands of mutations in the DNA of these genes.
When someone with a family pattern of hereditary breast and ovarian cancer wants genetic testing, it is important that testing begin with a family member who has already been diagnosed with breast or ovarian cancer. This is because a person who has had cancer is most likely to carry the altered gene causing the family's inherited cancer risk. Researchers call this person "the proband."
For this test, the laboratory sequences the proband's BRCA1 and BRCA2 genes and compares them to what is known to be "normal" sequences, to determine whether there has been a mutation.
Interpreting the Results
The results of DNA sequencing are not always easy to interpret. In some cases, this test reveals a mutation known to cause breast and ovarian cancer. In other cases it produces ambiguous results, which require additional tests of other family members in order to be useful.
DNA sequencing is considered the "gold standard" for testing. However, this test can still miss duplications or deletions within a gene. So, it is important to remember that even if this test does not find a deleterious mutation, it does not mean that a family is not at risk for breast or ovarian cancer. It just means that the cause for that family's cancer risk has not yet been found.
There are three types of possible results from this test: positive, negative, and ambiguous.
Positive ResultThe test has turned up what researchers call a "known deleterious change." One of the BRCA genes has a mutation and is producing an abnormal-functioning protein.
This means that the genetic culprit for a family's inherited cancer has been found, and other family members can be tested for the same mutation via single site testing.
Ambiguous ResultThis test has turned up a genetic changethat scientists don't know how to interpret. These types of mutations typically don't shorten the BRCA1 or BRCA2 proteins, but they do occur in regions of the gene that could be important for the protein to function properly.
Scientists refer to such mutations as "variants of unknown significance." The bottom line for this result is that, although a mutation has been found, it is unclear whether it is responsible for a family's breast and/or ovarian cancers.
Testing additional family members with DNA sequencing may help clarify the results of an ambigous test. If other family members with cancer have this same mutation, it suggests that the cancer might be related to the change. And if disease-free members of the family do not have this mutation, it further confirms the mutation's importance.
There are some known alterations in BRCA1 and BRCA2 that that are not associated with family histories of breast and ovarian cancer. These changes occur in more than 2 percent of the population . So a change in your DNA doesn't necessarily confer a higher risk for breast or ovarian cancer.
Negative ResultThere are two types of negative results:
- Unknown mutation. The DNA sequencing test has detected an alteration that doesn't appear to increase a person's chances of developing breast or ovarian cancer. Such mutations typically do not shorten the BRCA1 or BRCA2 gene's protein, and they tend to occur in regions of the gene that are not thought to be important to protein function. Scientists consider this a negative result because — even though a genetic change has been found — it is a change that is seen in families without breast or ovarian cancer as well, and is not believed to be associated with the disease.
- No mutation. The DNA sequencing test has failed to turn up any alterations in the BRCA1 and BRCA2 genes. There is still the possibility that there is a change in BRCA1 or BRCA2 that is not detectable by full sequencing. It is also possible that another – so far unidentified – gene is responsible for the cancer history in that particular family. For the person with this test result, it is important to pay careful attention to you family history when discussing screening recommendations with your health care provider.
Advantages and Limitations of Sequencing
DNA sequencing can provide important information for families with a high risk for breast and ovarian cancer. If the proband's test reveals a mutation, then other family members can be tested for the same mutation — a much less costly and time-consuming procedure than full sequencing. Testing for just this one mutation also produces a much less ambiguous result. Either the mutation is there, or it isn't. In addition, if a family member tests negative for the mutation, then he or she has not inherited the family's predisposition to cancer and can follow less stringent screening and prevention guidelines.
The disadvantage to DNA sequencing is that in addition to providing possibly ambiguous results, this test may miss some mutations that can occur in the BRCA1 and BRCA2 genes. For this reason, even negative test results are not as straightforward as they sound: If no alteration is detected in a high-risk individual, scientists don't know whether this is because the person truly doesn't have a mutation or because a mutation exists in a region the test doesn't examine. Either way, the negative test result may give a person a false sense of security when, in fact, they are still at very high risk.
Undetectable Changes in BRCA1 and BRCA2DNA sequencing can fail to detect some deletions or duplications in BRCA1 and BRCA2, which have been found in specific populations. Two years ago, a large deletion panel for 5 known rearrangements was added to the testing process. These particular deletions are present in individuals of Dutch and Northern European ancestry. These types of alterations account for a small percentage of breast and ovarian cancer in families.
Read more: One Family's Experience with DNA Sequencing
References:
Ford, D. et al. (1998). Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62(3): 676-89.
Ganguly, A. et al. (1997). Genetic testing for breast cancer susceptibility: frequency of BRCA1 and BRCA2 mutations. Genet Test 1(2): 85-90.
Geller, G. et al. (1997). Genetic testing for susceptibility to adult-onset cancer. The process and content of informed consent. JAMA 277(18): 1467-74.
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.
Stoppa-Lyonnet, D. et al. (1999). Genetic testing for breast cancer predisposition in 1999: which molecular strategy and which family criteria? Dis Markers 15(1-3): 67-8.
