In a series of 66 sporadic medullary thyroid carcinomas (MTC) we looked for mutations in RET, RAS and BRAF protooncogenes and correlated mutational analysis with the clinicopathological data of the patients. We performed PCR amplification and sequencing analysis of exons 5, 8, 1016 of RET, of the three mutational hotspots (codons 12, 13, and 61) of the H-, K-, and N-RAS genes, and of the mutational hotspot (codon 600) and exon 11 of the BRAF gene. Somatic RET mutations were found in 40/66 (60.6%) MTC, with exon 16 being the most frequently affected (52.5% of RET-positive tumours). Somatic RAS mutations were detected in 18 of 26 (69.2%) RET-negative MTC (15 cases had H-RAS and 3 cases K-RAS mutations). On the other hand, only one of 40 (2.5%) RET-positive MTC had a RAS mutation, namely in H-RAS. No mutations of N-RAS or BRAF were detected in all assessed tumour samples. MTC patients with mutations in RET exons 15 and 16 had higher prevalence and higher number of lymph node metastases, and presented more often multifocal tumours and persistent disease at last control than cases with other RET mutations. Patients having no RET mutations (either RAS-positive or RAS-negative) were at intermediate risk. Our results showed that activation of the protooncogenes RAS and RET represents alternative genetic events in sporadic MTC tumourigenesis. Updated mutational analysis of the RET- and RAS-negative cases will be provided at the meeting.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: Declaration of Funding: Bolsa Prof. E. Limbert SPEDM/Genzyme.