RET – Multiple Endocrine Neoplasia Type 2B

Multiple endocrine neoplasia type 2B (MEN 2B) is a highly penetrant autosomal-dominant cancer syndrome characterized by early-onset medullary thyroid carcinoma (MTC), pheochromocytoma, mucosal neuromas and marfanoid habitus. Germline activating mutations in RET (HGNC:9967) are causative for MEN 2B, with the M918T substitution accounting for more than 95% of cases. The association between RET and MEN 2B meets ClinGen criteria for a Definitive gene–disease relationship based on the identification of a single point mutation in 34 unrelated probands (PMID:7906417), familial segregation and concordant functional data.

Genetic evidence supports an autosomal-dominant inheritance mode with frequent de novo occurrence. The c.2753T>C (p.Met918Thr) variant has been observed in 34 unrelated MEN 2B patients (PMID:7906417), including 14 confirmed de novo cases. Segregation analysis in multiplex pedigrees demonstrates complete co-segregation with disease, and cross-sectional screening in five families revealed 14 additional affected first-degree relatives. Variant spectrum in MEN 2B is dominated by M918T; rare alternative alleles include A883F and tandem V804M/Y806C events, but none rival the prevalence or penetrance of M918T.

Functional studies establish RET^M918T as a constitutively active oncoprotein. RET with M918T exhibits ligand-independent autophosphorylation, enhanced kinase activity and potent transforming capacity in NIH3T3 and PC12 cell models, inducing focus formation and neurite outgrowth (PMID:8570194). Structural analyses show altered substrate specificity and engagement of PI3K/AKT and SFK signaling pathways. In vivo, RET^M918T exerts a selective advantage in spermatogonial stem cells, explaining male mutation bias and paternal age effect (PMID:22359510).

Patient-derived induced pluripotent stem cells harboring RET M918T recapitulate key MEN 2B features, including differentiation into pheochromocytoma-like and C‐cell lineages with hyperactivation of RET signaling (PMID:28925363). These cellular models enable mechanistic dissection and therapeutic screening, reinforcing the gain-of-function model of pathogenicity.

Conflicting evidence is minimal. A subset of patients with clinical MEN 2B features lack codon 918 mutations, suggesting phenotypic overlap with other RET alleles or non-RET loci (PMID:9270546). Low-penetrance variants such as K666N have been reported in indolent MTC, indicating allele-specific risk stratification may refine clinical management.

In summary, germline RET M918T is the predominant driver of MEN 2B, with robust genetic, segregation and functional data supporting a haploinsufficiency and dominant-active kinase mechanism. This definitive association underpins molecular diagnostics, informs prophylactic thyroidectomy recommendations and guides targeted therapies. Early RET genotyping improves patient outcome by enabling preclinical intervention before MTC onset.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1994 • Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B PMID:7906417
• Oncogene • 1995 • RET activation by germline MEN2A and MEN2B mutations PMID:8570194
• PLoS Genetics • 2012 • Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B PMID:22359510
• Stem Cell Research • 2017 • Generation of an induced pluripotent stem cell line from a patient with hereditary multiple endocrine neoplasia 2B (MEN2B) syndrome with “highest risk” RET mutation PMID:28925363

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