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. | 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 . 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
