The oncogenic activity of RET point mutants for follicular thyroid cells may account for the occurrence of papillary thyroid carcinoma in patients affected by familial medullary thyroid carcinoma.

Abstract

Activating germ-line point mutations in the RET receptor are responsible for multiple endocrine neoplasia type 2-associated medullary thyroid carcinoma (MTC), whereas somatic RET rearrangements are prevalent in papillary thyroid carcinomas (PTCs). Some rare kindreds, carrying point mutations in RET, are affected by both cancer types, suggesting that, under specific circumstances, point mutations in RET can drive the generation of PTC. Here we describe a family whose siblings, affected by both PTC and MTC, carried a germ-line point mutation in the RET extracellular domain, converting cysteine 634 into serine. We tested on thyroid follicular cells the transforming activity of RET(C634S), RET(K603Q), another mutant identified in a kindred with both PTC and MTC, RET(C634R) a commonly isolated allele in MEN2A, RET(M918T) responsible for MEN2B and also identified in kindreds with both PTC and MTC, and RET/PTC1 the rearranged oncogene that characterizes bona fide PTC in patients without MTC. We show that the various RET point mutants, but not wild-type RET, scored constitutive kinase activity and exerted mitogenic effects for thyroid PC Cl 3 cells, albeit at significantly lower levels compared to RET/PTC1. The low mitogenic activity of RET point mutants paralleled their reduced kinase activity compared to RET/PTC. Furthermore, RET point mutants maintained a protein domain, the intracellular juxtamembrane domain, that exerted negative effects on the mitogenic activity. In conclusion, RET point mutants can behave as dominant oncogenes for thyroid follicular cells. Their transforming activity, however, is rather modest, providing a possible explanation for the rare association of MTC with PTC.

• Authors: Rosa Marina Melillo, Anna Maria Cirafici, Valentina De Falco, Marie Bellantoni, Gennaro Chiappetta, Alfredo Fusco, Francesca Carlomagno, Antonella Picascia, Donatella Tramontano, Giovanni Tallini, Massimo Santoro
• Journal: The American journal of pathology (Am J Pathol) Vol. 165 Issue 2 Pg. 511-21 (Aug 2004) ISSN: 0002-9440 [Print] United States
• PMID: 15277225 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-ret
• Receptor Protein-Tyrosine Kinases
• Ret protein, rat

Topics

• Adenocarcinoma, Follicular (genetics, pathology)
• Adult
• Animals
• Carcinoma, Medullary (genetics, pathology)
• Carcinoma, Papillary (genetics, pathology)
• Cell Differentiation
• Cell Transformation, Neoplastic
• Cells, Cultured
• Epithelial Cells (metabolism, pathology)
• Female
• Gene Rearrangement
• Genetic Predisposition to Disease
• Germ-Line Mutation (genetics)
• Humans
• Male
• Multiple Endocrine Neoplasia Type 2a (genetics)
• Pedigree
• Point Mutation (genetics)
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins c-ret
• Rats
• Rats, Inbred F344
• Receptor Protein-Tyrosine Kinases (genetics)
• Thyroid Gland (metabolism, pathology)
• Thyroid Neoplasms (genetics, pathology)