Genetic Testing Interpretation of Test Results

Genetic testing for cancer and its role, benefits, and limitations are discussed in the counseling session both in terms of the scientific merits of understanding the genetic basis of cancer and, when appropriate, as it may apply to further characterizing the cancer risk within the proband's family. When possible, it is best to first consider testing an affected family member who meets the criteria for a hereditary cancer, as that individual is the one most likely to test positive. When a mutation is found, additional family members can be tested with an assay that specifically tests for that particular mutation.

There are four possible interpretations of a genetic test result (Table 25.5). If a known risk-associated mutation is found within a family, those family members who test positive for the mutation are considered "true positives." They are counseled that they are at increased risk for a spectrum of cancers, and options for risk management are discussed (see following). It must be emphasized that a positive mutation result is not a positive cancer test but rather a susceptibility estimate. A positive test result does, however, confirm a 50% chance of passing on the mutation to each biologic child of the carrier. A second outcome of a positive test result is the discovery of a variant of the gene of unknown clinical significance. These genes are truly altered but have not yet been clearly linked to disease risk and may represent neutral alter-

TABLE 25.5. Genetic test results.

True positive The person is a carrier of an alteration in a known cancer-predisposing gene.

True negative A person is not a carrier of a known cancer-

predisposing gene that has been positively identified in another family member.

Indeterminant A person is not a carrier of a known cancer-

predisposing gene and the carrier status of other family members is either also negative or is unknown.

Inconclusive A person is a carrier of an alteration in a gene that currently has no known significance.

ations in the gene structure that do not compromise its function. Over time, as more families are studied, most of these variants most likely can be separated into disease-related changes and benign changes, known as polymorphisms. Until then, families found to carry one of these variants must be counseled about the uncertain meaning of the result, and recommendations will be based on their family and personal history of disease. When a disease-related mutation has been identified in a family, subsequent family members who test negative for that mutation are thought to be "true negatives" whose risks for the relevant cancers are not increased over those of the general population. These family members may be spared the increased surveillance and/or consideration of prophylactic surgery offered to carriers. They can also be reassured that they will not pass on the deleterious mutation to their offspring. Finally, when no mutation is found in any family member (which is the most common situation), the meaning of a negative test result is ambiguous. It may mean that there truly is no mutation in the family and that the family history represents a clustering of sporadic cancers, it may mean a known disease-related mutation does exist in the family but no informative family members were available for testing, or it may mean that a mutation exists but cannot be detected by current technology. Again, counseling must emphasize the ambiguous nature of the test results. These families may still face a significantly increased risk of cancer and management should be based on other factors. A clear distinction is made between the probability of being a mutation carrier and the probability of developing cancer. Estimates of penetrance of the gene, that is, the chance that a mutation will actually result in cancer in a person, are also typically derived from small studies among narrowly defined families and are difficult to apply to any particular individual unless he or she matches the characteristics of the families studied. Information on other factors that may modify gene expression is rudimentary at this point for most of the genes identified.

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