Table 3. Percentage of Patients with Clinical Features of MEN2 by Subtype continued...
In a study of 44 families, seven families (16%) had cosegregation of MEN2A and HSCR1. The probability that individuals in a family with MEN2A and an exon 10 Cys mutation would manifest HSCR1 was estimated to be 6% in one series. Furthermore, in a multicenter international RET mutation consortium study, 6 of a total of 62 kindreds carrying either the C618R or C620R mutation also had HSCR.
A novel analytic approach employing family-based association studies coupled with comparative and functional genomic analysis revealed that a common RET variant within a conserved enhancer-like sequence in intron 1 makes a 20-fold greater contribution to HSCR compared with all known RET mutations. This mutation has low penetrance and different genetic effects in males and females. Transmission to sons and daughters leads to a 5.7-fold and 2.1-fold increase in susceptibility, respectively. This finding is consistent with the greater incidence of HSCR in males. Demonstrating this strong relationship between a common noncoding mutation in RET and the risk of HSCR also accounts for previous failures to detect coding mutations in RET-linked families.
Molecular Genetics of MEN2
MEN2 syndromes are the result of inherited mutations in the RET gene, located on chromosome region 10q11.2.[89,90,91] The RET gene is a proto-oncogene composed of 21 exons over 55 kilobase of genomic material.[92,93]
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.[95,96,97]
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.)