Activation of <i>RET</i> as a Dominant Transforming Gene by Germline Mutations of MEN2A and MEN2B

TLDR

Multiple endocrine neoplasia types 2A and 2B and familial medullary thyroid carcinoma are dominantly inherited cancer syndromes linked to mutations in the RET receptor‑like tyrosine kinase. Altered RET alleles act as transforming genes in NIH 3T3 cells via constitutive kinase activation, with MEN2A driving steady‑state dimerization and MEN2B modifying catalytic properties, thereby establishing germline transmission of dominant oncogenic RET.

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.