Prognostic Impact of miR-224 and RAS Mutations in Medullary Thyroid Carcinoma.

Elisabetta Cavedon,Simona Censi,Federica Vianello,Sara Watutantrige-Fernando,Maurizio Iacobone,Susi Barollo,Clara Benna,Davide Nacamulli,Francesca Galuppini,Stefania Zovato,Caterina Mian,Loris Bertazza,Gianmaria Pennelli

doi:10.1155/2017/4915736

Abstract

Little is known about the function of microRNA-224 (miR-224) in medullary thyroid cancer (MTC). This study investigated the role of miR-224 expression in MTC and correlated it with mutation status in sporadic MTCs. A consecutive series of 134 MTCs were considered. Patients had a sporadic form in 80% of cases (107/134). In this group, REarranged during transfection (RET) and rat sarcoma (RAS) mutation status were assessed by direct sequencing in the tumor tissues. Quantitative real-time polymerase chain reaction was used to quantify mature hsa-miR-224 in tumor tissue. RAS (10/107 cases, 9%) and RET (39/107 cases, 36%) mutations were mutually exclusive in sporadic cases. miR-224 expression was significantly downregulated in patients with the following: high calcitonin levels at diagnosis (p = 0.03, r = −0.3); advanced stage (p = 0.001); persistent disease (p = 0.001); progressive disease (p = 0.002); and disease-related death (p = 0.0001). We found a significant positive correlation between miR-224 expression and somatic RAS mutations (p = 0.007). Patients whose MTCs had a low miR-224 expression tended to have a shorter overall survival (log-rank test p = 0.005). On multivariate analysis, miR-224 represented an independent prognostic marker. Our data indicate that miR-224 is upregulated in RAS-mutated MTCs and in patients with a better prognosis and could represent an independent prognostic marker in MTC patients.

Highlights

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine cancer originating from parafollicular, calcitonin(Ct-) producing C-cells
We initially examined the clinical/pathological differences in relation to serum Ct levels at diagnosis, we considered the differences in miR-224 expression level in relation to the following: (a) clinical/pathological findings (CT level at diagnosis, nodal and distant involvement, and TNM stage); (b) patient’s outcome; and (c) somatic REarranged during transfection (RET) and rat sarcoma (RAS) mutations in sporadic MTCs
We found somatic RET mutations in 36% of cases of sporadic MTC (39/107), most of them located on exon 16 at codon 918 (M918T in 23/39; 59%)

Summary

Introduction

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine cancer originating from parafollicular, calcitonin(Ct-) producing C-cells. It accounts for 5–10% of all thyroid carcinomas with a global 10-year survival rate around 65% to 70%. About 75% of MTCs are sporadic, while the remainders are hereditary, due to germline mutations that activate the REarranged during transfection (RET) proto-oncogene [1]. Distinctive germinal RET mutations in the inherited forms and somatic RET mutations in sporadic cases represent the most important molecular markers for an adequate prognostic stratification of MTC patients [3,4,5,6]. It has been demonstrated that a combined analysis of somatic RET and Ki-67 is useful for identifying patients with

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Conclusion