Analysis of new molecular mechanism involved in MTC aggressiveness and progression
Medullary thyroid cancer (MTC) represents only 3-5% of thyroid cancers. The dominant oncogene mutated in MTC is proto-oncogene RET. The analysis of the genotype¿phenotype correlation clearly indicates that not all mutations of RET have same effect on MTC clinical features, and consequently patients shown different response to treatment.
A mutation in RET gene lead to constitutive activation and aberrant expression or activation of receptor, but also it can be involved in a specific molecular mechanisms that modulate RET expression. Most of the mechanisms by which RET expression is modulate are unknown.
In recent years have been studied a broad spectrum of molecular events involved in oncogene regulation that can drive tumorigenesis.
The aim of this project is to improve the knowledge of molecular mechanisms involved in regulation of RET proto-oncogene expression at genetic, expression and protein level.
For this aim, we would like to study the molecular mechanism of a new germ-line synonymous substitution on on RET proto-oncogene expression.
The germ-line synonymous substitution was harbored by a patient with a very aggressive form of MTC; synonymous substitution was found in-cis with another somatic gain-of-function RET mutation. We collected several data suggesting the implication of a new oncogenic mechanism by which synonymous mutations could strengthen activation of mutated oncogene. To demonstrate the mechanism by which synonymous substitution affects RET expression, we decide to performed several in vitro experiments using RET minigenes.