RET – Pheochromocytoma

RET proto-oncogene mutations are a definitive cause of hereditary pheochromocytoma, acting in an autosomal dominant manner with high penetrance for adrenal medullary tumors. ClinGen rates this association as Definitive based on over 100 unrelated probands, extensive multi-family segregation, and concordant functional studies demonstrating oncogenic activation of mutant RET kinase ([PMID:8103403]).

Genetic Evidence

Inheritance of pheochromocytoma due to RET follows an autosomal dominant pattern with variable age-related penetrance. Segregation analyses across multiple pedigrees have documented at least 41 additional affected relatives carrying pathogenic RET alleles ([PMID:14739494]). Case series report >130 probands with missense variants clustering in exons 10, 11 (extracellular cysteine-rich domain) and exon 16 (tyrosine kinase domain). Recurrent hotspot mutations include c.1902C>G (p.Cys634Trp) and c.2753T>C (p.Met918Thr), with founder effects in certain populations. We illustrate the variant spectrum by the missense mutation c.1833C>G (p.Cys611Trp) detected in exon 10 of a familial MEN2A-2 pheochromocytoma kindred ([PMID:14739494]).

Functional / Experimental Evidence

Pathogenic RET mutations induce ligand-independent disulfide-linked homodimerization, constitutive tyrosine kinase activation, and downstream MAPK/ERK signaling. Mutant proteins transform NIH3T3 fibroblasts and induce PC12 neuronal differentiation, recapitulating human disease phenotypes. Structural and biochemical assays confirm increased autophosphorylation, altered substrate specificity (e.g. enhanced Crk and Nck binding), and impaired receptor down-regulation for MEN2B (p.Met918Thr) alleles ([PMID:7906417], [PMID:9393871]). Animal and in vitro rescue experiments underscore RET’s oncogenic mechanism.

Conflicting Evidence

A minority of pheochromocytoma patients lack RET mutations despite syndromic features, and low-penetrance variants such as p.Tyr791Phe yield isolated pheochromocytoma without medullary thyroid carcinoma, challenging uniform pathogenic classification ([PMID:26639185]).

Integration & Conclusion

Decades of genetic and functional data firmly establish RET as a definitive driver of hereditary pheochromocytoma. Comprehensive RET testing guides risk stratification, familial screening, and early intervention. Key take-home: RET mutation screening is essential in pheochromocytoma patients regardless of age or apparent sporadic presentation to optimize clinical management and improve outcomes.

References

• International journal of urology • 1997 • Absence of RET proto-oncogene mutations in a father and son with pheochromocytoma and pancreatic islet cell tumor. PMID:9179691
• Endocrine Pathology • 2003 • Long-term follow up of a "sporadic" unilateral pheochromocytoma revealing multiple endocrine neoplasia MEN2A-2 in an elderly woman. PMID:14739494
• Proceedings of the National Academy of Sciences of the United States of America • 1994 • Single missense mutation in codon 918 of the RET proto-oncogene in sporadic medullary thyroid carcinomas. PMID:7906417
• European Journal of Endocrinology • 2004 • Multiple endocrine neoplasia 2A syndrome presenting as peripartum cardiomyopathy due to catecholamine excess. PMID:15588245
• Annales d'endocrinologie • 2015 • Questioning the pathogenic role of the pTyr791Phe mutation of the RET proto-oncogene: Insight from a case report. PMID:26639185
• Human Molecular Genetics • 1993 • Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. PMID:8103403

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