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

Endocr Relat Cancer. 2018 Mar;25(3):217-231. doi: 10.1530/ERC-17-0389. Epub 2018 Jan 3.

Abstract

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.

Keywords: circulating miRNA; medullary thyroid cancer; metastases; miR-375; prognostic biomarker.

Publication types

  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Thyroid Neoplasms / blood
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / pathology
  • Tumor Burden
  • Young Adult
  • ras Proteins / genetics

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • MIRN375 microRNA, human
  • MicroRNAs
  • Piperidines
  • Protein Kinase Inhibitors
  • Quinazolines
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • ras Proteins
  • vandetanib

Supplementary concepts

  • Thyroid cancer, medullary