Table 3. Percentage of Patients with Clinical Features of MEN2 by Subtype continued...
MEN2 is a well-defined hereditary cancer syndrome for which genetic testing is considered an important part of the management for at-risk family members. It meets the criteria related to indications for genetic testing for cancer susceptibility outlined by the American Society of Clinical Oncology in its most recent genetic testing policy statement. At-risk individuals are defined as first-degree relatives (parents, siblings, and children) of a person known to have MEN2. Testing allows the identification of people with asymptomatic MEN2 who can be offered risk-reducing thyroidectomy and biochemical screening as preventive measures. A negative mutation analysis in at-risk relatives, however, is informative only after a disease-causing mutation has been identified in an affected relative. (Refer to the PDQ summary Cancer Genetics Risk Assessment and Counseling for more information.) Because early detection of at-risk individuals affects medical management, testing of children who have no symptoms is considered beneficial.[98,99] (Refer to the Genotype-Phenotype Correlations and Risk Stratification section of this summary for more information about clinical management of at-risk individuals.)
Germline DNA testing for RET mutations is generally recommended to all individuals with a diagnosis of MTC, regardless of whether there is a personal or family history suggestive of MEN2.[23,100] Approximately 95% of patients with MEN2A or MEN2B will have an identifiable germline RET mutation. For FMTC the detection rate is slightly lower at 88%. Importantly, 1% to 7% of apparently sporadic cases of MTC will carry a germline RET mutation, underscoring the importance of testing all cases.[18,19,20,21]
There is no evidence for the involvement of other genetic loci, and all mutation-negative families analyzed to date have demonstrated linkage to the RET gene. For families that do not have a detectable mutation, clinical recommendations can be based on the clinical features in the affected individual and in the family.
There is considerable diversity in the techniques used and the approach to RET mutation testing among the various laboratories that perform this procedure. Methods used to detect mutations in RET include polymerase chain reaction (PCR) followed by restriction enzyme digestion of PCR products, heteroduplex analysis, single-stranded conformation polymorphism (SSCP) analysis, denaturing high-performance liquid chromatography (DHPLC), and DNA sequencing.[101,102,103,104] Most testing laboratories, at a minimum, offer testing using a targeted exon approach; that is, the laboratories look for mutations in the exons that are most commonly found to carry mutations (exons 10, 11, 13, 14, 15 and 16). Other laboratories offer testing for all exons. If targeted exon testing in a family with a high clinical suspicion for MEN2 is normal, sequencing of the remaining exons can then be performed.
These differences in mutation detection method and targeted versus full gene testing represent important considerations for selecting a laboratory to perform a test and in interpreting the test result. (Refer to the PDQ summary Cancer Genetics Risk Assessment and Counseling for more information on clinical validity.)