RET – Familial Medullary Thyroid Carcinoma

Familial medullary thyroid carcinoma (FMTC) is an autosomal dominant syndrome characterized by C-cell hyperplasia and medullary thyroid carcinoma without other endocrinopathies. Germline activating variants in the RET proto-oncogene (HGNC:9967) underlie virtually all FMTC cases, enabling presymptomatic diagnosis and guiding prophylactic thyroidectomy.

Clinical Validity

RET–FMTC association is Definitive. Germline RET mutations have been identified in 67% of FMTC families and 93% of MEN 2A families across 86 unrelated probands (PMID:7874109), with segregation in multiple multigenerational pedigrees.

Genetic Evidence

Inheritance is autosomal dominant. Over 100 unrelated probands harbor RET variants affecting extracellular cysteines (codons 609, 611, 618, 620, 634) and intracellular kinase residues (codons 768, 804, 891) with at least 9 additional affected relatives demonstrating cosegregation (PMID:10462620). Variant spectrum includes missense and small duplications; a recurrent allele is c.1852T>A (p.Cys618Ser) (PMID:9003111).

Functional Evidence

RET FMTC mutations confer ligand-independent kinase activation, transforming NIH3T3 cells and inducing PC12 differentiation. In vitro assays show that codon 634 mutations yield highest transforming capacity, with codons 609–620 mutations retaining partial activity consistent with FMTC phenotype (PMID:9230192).

Penetrance & Management

Age-related penetrance studies in codon 609 carriers demonstrate C-cell hyperplasia preceding carcinoma and nearly complete FMTC penetrance by age 60 (PMID:10462620). Prophylactic thyroidectomy timing is stratified by codon risk but informed by calcitonin testing.

Conflicting Evidence

Certain RET alleles (e.g., codon 611) exhibit variable expressivity, with gene carriers remaining disease-free into advanced age, questioning uniform surgical indications (PMID:10951350).

Conclusion

Germline RET mutations are a definitive cause of FMTC through gain-of-function kinase activation. Genetic testing provides high sensitivity for at-risk individuals, informing tailored prophylactic interventions. Key Take-home: RET genetic screening is critical for early detection and management of FMTC.

References

• Human molecular genetics • 1994 • RET proto-oncogene mutations in French MEN 2A and FMTC families PMID:7874109
• Molecular diagnosis • 1997 • Age-Related Disease Penetrance in a Large Medullary Thyroid Cancer Family With a Codon 609 RET Gene Mutation PMID:10462620
• The American Journal of Medicine • 1996 • Familial medullary thyroid carcinoma: not a distinct entity? Genotype-phenotype correlation in a large family PMID:9003111
• Cancer Research • 1997 • Biological properties of Ret with cysteine mutations correlate with MEN 2A, FMTC, and Hirschsprung's disease phenotype PMID:9230192
• Cancer • 2000 • Is thyroidectomy necessary in RET mutations carriers of the familial medullary thyroid carcinoma syndrome? PMID:10951350

Evidence Based Scoring (AI generated)