Molecular Genetics of MEN 2
MEN 2 syndromes are the result of inherited mutations in the RET gene, located on chromosome region 10q11.2.[76,77,78] The RET gene is a proto-oncogene composed of 21 exons over 55 kilobase of genomic material.[79,80]
RET encodes a receptor tyrosine kinase with extracellular, transmembrane, and intracellular domains. Details of RET receptor and ligand interaction in this signaling pathway have been reviewed. Briefly, the extracellular domain consists of a calcium-binding cadherin-like region and a cysteine-rich region that interacts with one of four ligands identified to date. These ligands, e.g., glial-derived neurotropic factor (GDNF), neurturin (NTN), persephin (PSF), and artemin (ATF), also interact with one of four coreceptors in the GFR-alpha family. The tyrosine kinase catalytic core is located in the intracellular domain, which causes downstream signaling events through a variety of second messenger molecules. Normal tissues contain transcripts of several lengths.[82,83,84]
MEN 2 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 MEN 2. Testing allows the identification of people with asymptomatic MEN 2 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.[85,86] 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 MEN 2.[22,87] Approximately 95% of patients with MEN 2A or MEN 2B 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.[17,18,19,20]
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.