RET p.G548V mutation identified in sporadic and hereditary pheochromocytomas: a study of prevalence and activation of MAPK pathway and metilation profile

Abstract

The RET gene is an oncogene located on chromosome 10q11.2, contains 21 exons and encodes a transmembrane receptor with tyrosine kinase activity that is connected to signaling pathways involving growth, migration and cell growth. Activating RET mutations in germline cell lineages are responsible for receptor activation independent of ligand interactions and are associated with an autosomal dominant hereditary syndrome called multiple endocrine neoplasia type 2 (MEN 2), which can be classified into three subtypes: MEN 2A, MEN 2B and familial medullary thyroid carcinoma (FMTC). Recently, our group described a novel heterozygous mutation in exon 8 of RET gene associated with FMTC, which leads to the replacement of a glycine by a cysteine at codon 533 (G533C). Later a member of the family with FMTC presented diagnosis of pheochromocytoma, changing therefore the classification of the family for MEN 2A. With the goal of understanding the genetic mechanisms associated with the penetrance of pheochromocytoma in this patient, we investigate additional mutations in the RET gene in DNA isolated from the tumor. Besides G533C RET mutation, two new mutations: G548V (exon 8) and S556T (exon 9) were identified. These data, together with the literature on mutations in exon 8 and its genotype-phenotype, suggests that they are more aggressive and more prevalent than previously imagined. Therefore, this project aims to understand the overall role of RET gene mutations identified by the group and associated with MEN 2A syndrome, by checking the prevalence and analysis of phosphorylation and methylation profile of the mutated RET protein. (AU)