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Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B
M Santoro1, F Carlomagno, A Romano
1Centro di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (CNR), Napoli, Italy.
Abstract:
Multiple endocrine neoplasia types 2A and 2B (MEN2A and MEN2B) and familial medullary thyroid carcinoma are dominantly inherited cancer syndromes. All three syndromes are associated with mutations in RET, which encodes a receptor-like tyrosine kinase. The altered RET alleles were shown to be transforming genes in NIH 3T3 cells as a consequence of constitutive activation of the RET kinase. The MEN2A mutation resulted in RET dimerization at steady state, whereas the MEN2B mutation altered RET catalytic properties both quantitatively and qualitatively. Oncogenic conversion of RET in these neoplastic syndromes establishes germline transmission of dominant transforming genes in human cancer.
Insights
Multiple endocrine neoplasia (MEN2A and MEN2B) and familial medullary thyroid carcinoma are inherited cancer syndromes caused by RET gene mutations. These mutations lead to constitutive activation of the RET kinase, driving tumor formation.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Multiple endocrine neoplasia types 2A and 2B (MEN2A and MEN2B) and familial medullary thyroid carcinoma are inherited cancer syndromes.
- These syndromes are linked to mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase.
Purpose of the Study:
- To investigate the transforming potential of mutated RET alleles.
- To understand the molecular mechanisms by which RET mutations lead to cancer.
Main Methods:
- NIH 3T3 cell transformation assays.
- Analysis of RET kinase activity, dimerization, and catalytic properties.
Main Results:
- Mutated RET alleles act as transforming genes in NIH 3T3 cells due to constitutive kinase activation.
- MEN2A mutations cause steady-state RET dimerization.
- MEN2B mutations alter RET catalytic properties quantitatively and qualitatively.
Conclusions:
- Oncogenic RET mutations in these syndromes represent germline transmission of dominant transforming genes.
- Constitutive RET activation is a key mechanism in the pathogenesis of MEN2A, MEN2B, and familial medullary thyroid carcinoma.