Unfortunately, even with this information, there is often insufficient evidence to document the significance of a specific variant and further clarifying research is required.
If there is no close, living, affected relative to undergo testing, or the living affected relative declines testing, other options may be discussed with the patient and the testing laboratory. These generally involve weighing the availability and reliability of testing the stored tissue of a deceased relative or testing an unaffected person without prior testing of an affected family member. Tests done on stored tissue are technically difficult and may not yield a definitive result. Testing an unaffected person without prior testing of an affected relative often is uninformative because a negative test does not rule out the presence of a cancer susceptibility gene in the family or the subject.
Testing in families with a documented deleterious mutation
Genetic susceptibility testing for a documented deleterious mutation in the family can be very informative and will yield one of the following two results (see Figure 2):
- Positive for the familial mutation.
- Negative for the familial mutation.
If the familial mutation is detected in a family member, their cancer risks are based on penetrance data for mutations in that specific gene. If the documented mutation is not found in a family member, the risk of cancer in that individual is equivalent to cancer risk in the general population. However, other risk factors and family history from the side of the family not associated with the documented mutation may increase the cancer risk above the general population levels.
In summary, genetic education and counseling includes identifying the most informative person in the family to test, which may be an affected family member rather than the individual seeking genetic services. In addition, counseling includes a discussion of the limitations of the test and all possible test outcomes, as well as the consequences of identifying a variant of unknown clinical significance.
Genetic testing and assisted reproductive technology
Advances in reproductive technology have enabled predisposition cancer genetic testing to be performed in the prenatal setting using chorionic villus sampling and amniocentesis, and in the preimplantation setting using preimplantation genetic diagnosis.[4,5,6] A literature review coupled with a brief survey found 55 case reports of prenatal or preimplantation diagnosis performed for cancer predisposition for more than 12 familial cancer syndromes. In a telephone survey of thirteen centers listed in an online resource as providing preimplantation genetic diagnosis, nine reported they provided this service for cancer predisposition syndromes.
Reproductive medicine used in the context of predisposition genetic testing for cancer risk raises important ethical, legal and social issues. A proposed analytic framework recommends considering the following issues:
- Does the cancer syndrome include childhood malignancies or significant morbidity or mortality at an early age?
- What is the penetrance associated with the gene mutation?
- How severe is the syndrome phenotype?
- Are there interventions available that decrease the mutation-associated cancer risk or are proven to detect cancer early when it is in a treatable form?