Chapter 079. Cancer Genetics (Part 5) While most autosomal dominant inherited cancer syndromes are due to mutations in tumor-suppressor genes (Table 79-1), there are a few interesting exceptions. Multiple endocrine neoplasia type II, a dominant disorder characterized by pituitary adenomas, medullary carcinoma of the thyroid, and (in some pedigrees) pheochromocytoma, is due to gain-of-function mutations in the protooncogene RET on chromosome 10. Similarly, gain-of-function mutations in the tyrosine kinase domain of the MET oncogene lead to hereditary papillary renal carcinoma. Interestingly, loss-of-function mutations in the RET gene cause a completely different disease, Hirschsprung's disease [aganglionic megacolon (Chaps. 291 and 345)]. Although the Mendelian forms of cancer have taught us much about the mechanisms of growth control, most forms of cancer do not follow simple patterns of inheritance. In many instances (e.g., lung cancer), a strong environmental contribution is at work. Even in such circumstances, however, some individuals may be more genetically susceptible to developing cancer, given the appropriate exposure, due to the presence of modifier alleles. Genetic Testing for Familial Cancer The discovery of cancer susceptibility genes raises the possibility of DNA testing to predict the risk of cancer in individuals of affected families. An algorithm for cancer risk assessment and decision-making in high-risk families using genetic testing is shown in Fig. 79-6. Once a mutation is discovered in a family, subsequent testing of asymptomatic family members can be crucial in patient management. A negative gene test in these individuals can prevent years of anxiety in the knowledge that their cancer risk is no higher than that of the general population. On the other hand, a positive test may lead to alteration of clinical management, such as increased frequency of cancer screening and, when feasible and appropriate, prophylactic surgery. Potential negative consequences of a positive test result include psychological distress (anxiety, depression) and discrimination (insurance, employment). Testing should therefore not be conducted without counseling before and after disclosure of the test result. In addition, the decision to test should depend on whether effective interventions exist for the particular type of cancer to be tested. Despite these caveats, genetic cancer testing for some cancer syndromes already appears to have greater benefits than risks, and many companies now offer testing for various genes associated with the predisposition to breast cancer (BRCA1 and BRCA2), melanoma (p16INK4), and colon cancer (APC and the HNPCC genes). Figure 79-6 Algorithm for genetic testing in a family with cancer predisposition. The key step is the identification of a mutation in a cancer patient, which allows testing of asymptomatic family members. Asymptomatic family members who test positive may require increased screen ing or surgery, whereas others are at no greater risk for cancer than the general population. Because of the inherent problems of genetic testing such as cost, specificity, and sensitivity, it is not yet appropriate to offer these tests to the general population. However, testing may be appropriate in some subpopulations with a known increased risk, even without a defined family history. For example, two mutations in the breast cancer susceptibility gene BRCA1, 185delAG and 5382insC, exhibit a sufficiently high frequency in the Ashkenazi Jewish population that genetic testing of an individual of this ethnic group may be warranted. It is important that genetic test results be communicated to families by trained genetic counselors. To ensure that the families clearly understand its advantages and disadvantages and the impact it may have on their management and psyche, genetic testing should never be done before counseling. Significant expertise is needed to communicate the results of genetic testing to families. For example, one common mistake is to misinterpret the result of negative genetic tests. For many cancer predisposition genes, the sensitivity of genetic testing is only ≤70% (i.e., of 100 kindreds tested, disease-causing mutations can be identified in only 70). Therefore, such testing should in general begin with an affected member of the kindred (the youngest family member still alive who has had the cancer of interest). If a mutation is not identified in this individual, then the test should be reported as noninformative (Fig. 79-6) rather than negative (because it is possible that the mutation in this individual is not detectable by standard genetic assays for purely technical reasons). On the other hand, if a mutation can be identified in this individual, then testing of other family members can be performed, and the sensitivity of such subsequent tests will be 100% (because the mutation in the family is in this case known to be detectable by the assay methods used). . Chapter 079. Cancer Genetics (Part 5) While most autosomal dominant inherited cancer syndromes are due to mutations in tumor-suppressor. Familial Cancer The discovery of cancer susceptibility genes raises the possibility of DNA testing to predict the risk of cancer in individuals of affected families. An algorithm for cancer. [aganglionic megacolon (Chaps. 291 and 3 45)] . Although the Mendelian forms of cancer have taught us much about the mechanisms of growth control, most forms of cancer do not follow simple patterns