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, Hirschsprungs disease [aganglionic megacolon (Chaps. 291 and 345)].Although the Mendelian forms of cancer...
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Chapter 079. Cancer Genetics (Part 5) Chapter 079. Cancer Genetics (Part 5) While most autosomal dominant inherited cancer syndromes are due tomutations in tumor-suppressor genes (Table 79-1), there are a few interestingexceptions. Multiple endocrine neoplasia type II, a dominant disordercharacterized by pituitary adenomas, medullary carcinoma of the thyroid, and (insome pedigrees) pheochromocytoma, is due to gain-of-function mutations in theprotooncogene RET on chromosome 10. Similarly, gain-of-function mutations inthe tyrosine kinase domain of the MET oncogene lead to hereditary papillary renalcarcinoma. Interestingly, loss-of-function mutations in the RET gene cause acompletely different disease, Hirschsprungs disease [aganglionic megacolon(Chaps. 291 and 345)]. Although the Mendelian forms of cancer have taught us much about themechanisms of growth control, most forms of cancer do not follow simple patternsof inheritance. In many instances (e.g., lung cancer), a strong environmentalcontribution is at work. Even in such circumstances, however, some individualsmay be more genetically susceptible to developing cancer, given the appropriateexposure, due to the presence of modifier alleles. Genetic Testing for Familial Cancer The discovery of cancer susceptibility genes raises the possibility of DNAtesting to predict the risk of cancer in individuals of affected families. Analgorithm for cancer risk assessment and decision-making in high-risk familiesusing genetic testing is shown in Fig. 79-6. Once a mutation is discovered in afamily, subsequent testing of asymptomatic family members can be crucial inpatient management. A negative gene test in these individuals can prevent years ofanxiety in the knowledge that their cancer risk is no higher than that of the generalpopulation. On the other hand, a positive test may lead to alteration of clinicalmanagement, such as increased frequency of cancer screening and, when feasibleand appropriate, prophylactic surgery. Potential negative consequences of apositive test result include psychological distress (anxiety, depression) anddiscrimination (insurance, employment). Testing should therefore not beconducted without counseling before and after disclosure of the test result. Inaddition, the decision to test should depend on whether effective interventionsexist for the particular type of cancer to be tested. Despite these caveats, geneticcancer testing for some cancer syndromes already appears to have greater benefitsthan risks, and many companies now offer testing for various genes associatedwith 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 allowstesting of asymptomatic family members. Asymptomatic family members whotest positive may require increased screening or surgery, whereas others are at nogreater 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 thegeneral population. However, testing may be appropriate in some subpopulationswith a known increased risk, even without a defined family history. For example,two mutations in the breast cancer susceptibility gene BRCA1, 185delAG and5382insC, exhibit a sufficiently high frequency in the Ashkenazi Jewishpopulation that genetic testing of an individual of this ethnic group may bewarranted. It is important that genetic test results be communicated to families bytrained genetic counselors. To ensure that the families clearly understand itsadvantages and disadvantages and the impact it may have on their managementand psyche, genetic testing should never be done before counseling. Significantexpertise is needed to communicate the results of genetic testing to families. Forexample, one common mistake is to misinterpret the result of negative genetictests. For many cancer predisposition genes, the sensitivity of genetic testing isonly ≤70% (i.e., of 100 kindreds tested, disease-causing mutations can beidentified in only 70). Therefore, such testing should in general begin with anaffected member of the kindred (the youngest family member still alive who hashad the cancer of interest). If a mutation is not identified in this individual, thenthe 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 bystandard genetic assays for purely technical reasons). On the other hand, if amutation can be identified ...