MOLECULAR GENETICS OF MEN 2
The MEN 2 locus was mapped to 10q11.2 and, subsequently, germline gain-of-function mutations in the RET proto-oncogene were found in probands with MEN 2A, MEN 2B, and FMTC (Gardner et al. 1993; Mulligan et al.
1993; Eng et al. 1994, 1995a, b; Bolino et al. 1995; Santoro et al. 1995; Zbuk and Eng 2007; Kloos et al. 2009).
Before the identification of RET as the MEN 2 susceptibility gene, the clinical penetrance of MEN 2A was said to be 70 % by the age of 70 years (Ponder et al. 1988). However, when molecular diagnosis became possible, the penetrance of MEN 2A when biochemical tests were used was found to be 100 % by the age of 70 years (Easton et al. 1989). Similarly, although early epidemiologic studies suggested that approximately 25 % of all MTC cases were due to MEN 2, when RET was identified, individuals with MTC tested without family history details or clinical details had a germline mutation frequency of approximately 25 % (Decker et al. 1995). Other studies have found frequencies ranging from 5 to 10 % (Eng et al. 1995; Wohlik et al. 1996; Schuffenecker et al. 1997; Wiench et al. 2001; Kloos et al. 2009). A population-based series of apparently sporadic PC, defined as no family history and no syndromic features, found a 5 % frequency of germline RET mutations (Neumann et al. 2002). Germline RET mutations have been identified in >95 % of all MEN 2, with 98 % of MEN 2A probands, 97 % in MEN 2B, and 85 % in FMTC (Eng et al. 1996a, b; Gimm et al. 1997; Smith et al. 1997; Kloos et al. 2009).
The characteristic mutational spectrum found in MEN 2A includes missense mutations in one of cysteine codons 609, 611, 618, 620 (exon 10), or 634 (exon 11) (Eng et al. 1996a, b; Kloos et al. 2009; Moline and Eng 2011). Approximately 85 % of MEN 2A individuals carry a codon 634 mutation (Eng et al. 1996a, b; Kloos et al. 2009; Moline and Eng 2011).
Genotype-phenotype analyses reveal that codon 634 mutations are associated with the presence of PC and HPT (Eng et al. 1996a, b; Zbuk and Eng 2007; Kloos et al. 2009), and the C634R mutation is most often associated with the development of HPT (Mulligan et al. 1994; Eng et al. 1996a, b; Schuffenecker et al. 1998; Kloos et al. 2009). Rare “one-off” missense mutations seen in MEN 2A include those involving codons 630 and 790 (Eng et al. 1996a, b; Eng 1999), although the codons 790 and 791 mutations may be polymorphisms (Erlic et al. 2010). FMTC-associated mutations occur at the same cysteine codons as those in MEN 2A, although mutations at codons 609–620 are more frequent in FMTC than MEN 2A. The C634R mutation is associated with HPT, so FMTC families have C634Y and other 634 mutations (Eng et al. 1996a, b; Zbuk and Eng 2007; Kloos et al. 2009). Germline mutations found almost exclusively in FMTC include E768day (exon 13), V804L, and V804M (exon 14), although one family segregating V804L has been described with older-onset unilateral PC in 2 members (Eng et al. 1996a, b; Nilsson et al. 1999; Kloos et al. 2009). Germline M918T and A883F mutations occur in 95 and 2 %, respectively, of MEN 2B patients (Eng et al. 1996a, b; Gimm et al. 1997; Smith et al. 1997) and never in MEN 2A or FMTC. Interestingly, at least four MEN 2B patients appear to carry a V804M mutation in the presence of a RET variant of unknown significance (Miyauchi et al. 1999; Kloos et al. 2009).
Variable penetrance is apparent: RET codons 918, 883, and 634 mutations have the highest penetrance, predisposing to MEN 2B and MEN 2A with MTC, PC, and HPT involvement (Eng et al. 1996a, b; Eng 2000b; Kloos et al. 2009). Mutations at codons 609–620 have a broad range of penetrance and expressivity, with 50 % penetrance by the age of 36 years for MTC, 68 years for pheochromocytoma, and 82 years for HPT (Frank-Raue et al. 2011), and penetrance for MTC by 50 years ranged from 60 % for codon 611 mutations to 86 % for codon 620 mutations.