Circulating miR-375 as a novel prognostic marker for metastatic medullary thyroid cancer patients

• Published in: Endocrine-related cancer Vol. 25; no. 3; pp. 217 - 231
• Main Authors: Romeo, Paola, Colombo, Carla, Granata, Roberta, Calareso, Giuseppina, Gualeni, Ambra Vittoria, Dugo, Matteo, De Cecco, Loris, Rizzetti, Maria Grazia, Zanframundo, Angela, Aiello, Antonella, Carcangiu, Maria Luisa, Gloghini, Annunziata, Ferrero, Stefano, Licitra, Lisa, Greco, Angela, Fugazzola, Laura, Locati, Laura Deborah, Borrello, Maria Grazia
• Format: Journal Article
• Language: English
• Published: England Bioscientifica Ltd 01.03.2018
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents - therapeutic use; Biomarkers, Tumor - blood; Carcinoma, Neuroendocrine - blood; Carcinoma, Neuroendocrine - genetics; Carcinoma, Neuroendocrine - pathology; Female; Humans; Male; MicroRNAs - blood; Middle Aged; Piperidines - therapeutic use; Prognosis; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-ret - genetics; Quinazolines - therapeutic use; ras Proteins - genetics; Thyroid Neoplasms - blood; Thyroid Neoplasms - genetics; Thyroid Neoplasms - pathology; Tumor Burden; Young Adult; medullary thyroid cancer; circulating miRNA; metastases; prognostic biomarker; miR-375
• ISSN: 1351-0088; 1479-6821; 1479-6821
• DOI: 10.1530/ERC-17-0389

This study aimed to identify circulating miRNAs as novel non-invasive biomarkers for prognosis and vandetanib response in advanced medullary thyroid cancer (MTC) patients. We prospectively recruited two independent cohorts of locally advanced/metastatic MTC patients including a subgroup of vandetanib-treated subjects: a discovery cohort (n = 20), including matched plasma/tissue samples (n = 17/20), and a validation cohort, yielding only plasma samples (n = 17). Plasma samples from healthy subjects (n = 36) and MTC patients in remission (n = 9) were used as controls. MTC (n = 17 from 8 patients included in discovery cohort) and non-neoplastic thyroid specimens (n = 3) were assessed by microarray profiling to identify candidate circulating miRNAs. qRT-PCR and in situ hybridization were carried out to validate the expression and localization of a selected miRNA within tissues, and qRT-PCR was also performed to measure miRNA levels in plasma samples. By microarray analysis, we identified 51 miRNAs differentially expressed in MTC. The most overexpressed miR, miR-375, was highly expressed by C cells compared to other thyroid cells, and more expressed in MTC than in reactive C-cell hyperplasia. MTC patients had significantly higher miR-375 plasma levels than healthy controls (P < 0.0001) and subjects in remission (P = 0.0004) as demonstrated by qRT-PCR analysis. miR-375 plasma levels were not predictive of vandetanib response, but, notably, high levels were associated with significantly reduced overall survival (HR 10.61, P < 0.0001) and were a strong prognostic factor of poor prognosis (HR 6.24, P = 0.00025) in MTC patients. Overall, our results unveil plasma miR-375 as a promising prognostic marker for advanced MTC patients, to be validated in larger cohorts.