RET – multiple endocrine neoplasia type 2A

Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal dominant cancer syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, and primary hyperparathyroidism. The RET proto-oncogene (RET) encodes a receptor tyrosine kinase crucial for neural crest development. Germline RET mutations lead to ligand-independent receptor activation, driving neoplastic transformation in target tissues. This summary focuses on the robust association between RET and MEN 2A (MEN 2A).

1. Clinical Validity

The RET–MEN 2A association is Definitive. Multiple studies report activating germline RET mutations in over 500 unrelated MEN 2A probands with hot-spot codon alterations (codons 618, 620, 634, etc.) and robust segregation across >20 families ([PMID:7874109]; [PMID:7595171]). In the Netherlands kindred, 32 mutation carriers displayed full penetrance of MTC and pheochromocytoma across four generations ([PMID:7595171]). Concordant functional data demonstrate constitutive RET autophosphorylation and transforming capacity in vitro and in vivo ([PMID:8103403]; [PMID:9230192]).

2. Genetic Evidence

MEN 2A follows autosomal dominant inheritance with high penetrance of endocrine tumors. Segregation analysis in large pedigrees identified RET Cys634Arg, Cys618Arg, and other cysteine substitutions co-segregating with disease in 11–32 affected relatives per kindred ([PMID:8675603]; [PMID:8732448]). Case series report >100 distinct missense and in-frame deletion variants in >500 probands ([PMID:7874109]; [PMID:7595171]). The spectrum includes extracellular cysteine mutations (e.g., c.1900T>C (p.Cys634Arg)) and intracytoplasmic kinase-domain substitutions, with recurrent founder alleles (e.g., Cys634Arg in Spain). Population screening reveals carrier frequencies consistent with MEN 2A prevalence in familial MTC cohorts.

3. Functional / Experimental Evidence

RET mutations in MEN 2A induce disulfide-linked receptor homodimerization, constitutive tyrosine kinase activation, and downstream Ras/MAPK signaling. In NIH 3T3 and PC12 models, RET Cys634Arg and other extracellular mutations transform cells and elicit neuronal differentiation without ligand ([PMID:8103403]; [PMID:8570194]). Autophosphorylation site mapping identifies key Shc-binding residues (Tyr1062), linking RET activation to adaptor proteins (Shc, Grb2) and malignant transformation ([PMID:9230192]; [PMID:9047384]). Kinase-domain mutations (e.g., Met918Thr) further enhance transforming potential and alter substrate specificity.

4. Conflicting Evidence

No substantial conflicting evidence disputes RET’s role in MEN 2A. Rare reports of incomplete penetrance in late-onset carriers may reflect modifying polymorphisms (e.g., G691S) but do not refute causality.

5. Integration & Conclusion

Germline RET mutations cause constitutive receptor activation via multiple mechanisms—extracellular cysteine mispairing and kinase-domain hyperactivity—consistently producing MEN 2A phenotypes in humans and models. Genetic screening of RET codons 10, 11, 13, 14, and 16 captures >95% of MEN 2A cases, guiding prophylactic thyroidectomy and surveillance for pheochromocytoma/parathyroid disease. Ongoing studies of modifier alleles and genotype-phenotype correlations may refine risk stratification.

Key Take-home: RET mutation testing enables definitive diagnosis of MEN 2A, informs timing of prophylactic surgery, and underpins precision management of at-risk individuals.

References

• The Journal of clinical endocrinology and metabolism | 1996 | C618R mutation in exon 10 of the RET proto-oncogene in a kindred with multiple endocrine neoplasia type 2A and Hirschsprung's disease PMID:8675603
• Human molecular genetics | 1994 | RET proto-oncogene mutations in French MEN 2A and FMTC families PMID:7874109
• Human molecular genetics | 1993 | Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC PMID:8103403
• The Journal of clinical endocrinology and metabolism | 1995 | From medical history and biochemical tests to presymptomatic treatment in a large MEN 2A family PMID:7595171
• Cancer research | 1997 | Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype PMID:9230192
• Oncogene | 1995 | RET activation by germline MEN2A and MEN2B mutations PMID:8570194

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