Hotspot Mutational Spectrum of RET Proto-Oncogene in Hereditary Medullary Thyroid Carcinoma

Introduction: Thyroid carcinoma is the most common endocrine tumor. Medullary thyroid carcinoma (MTC) accounts for 5-10% of all thyroid cancer. It occurs in both hereditary (25%, hMTC) and sporadic (75%, sMTC) forms which are associated with RET proto-oncogene gain of function mutations.Aim: The goal of this study was to identify hot spot mutations of RET in hMTC patients. Material and methods: This study included 39FMTC, 8MEN2A, 3MEN2B, 4pheochromocytoma (54 index cases), and 80 relatives (totally 134 individuals). Genomic DNA was extracted by Salting Out/Proteinase K method. Mutation detection forsix exons of RET (10, 11, 13, 14, 15, 16) were carried out using PCR and direct DNA sequencing.Results: A total of 15 different types of RET missense mutations were identified in 43 patients and 19 relatives. All of the MEN2A patients had mutations in codon 634, including p.C634Y (four patients), p.C634R (two patients), p.C634S (two patients). In FMTCs, the most common hot spot mutations were in exon 10 (p.C611Y, three patients) andexon 11 (p.C634Y, six patients). Only one mutation was detected in exon 13 (p.L790F) and exon 15 (p.R886Q) in FMTC.The p.M918T mutation was found in all MEN2B patients. The G691S/S904S haplotype was identified in 34 patients and 37relatives. Conclusion: According to this study, exons 11 and 10 were the most frequently mutated exons of RET in hMTC patients, in our population. Apparently, there is different mutational pattern in this gene which could be considered in the RET mutation screening for MTC patients and their families in the population.

کلیدواژه ها:

Medullary thyroid cancer ، RET proto-oncogene ، Germline mutation ، hot spot