Circulating miR-375 as a novel prognostic marker for metastatic medullary thyroid cancer patients
2018
This study aimed to identify circulating miRNAs as novel non-invasive biomarkers for prognosis and
vandetanibresponse 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-375plasma levels than healthy controls (P < 0.0001) and subjects in remission (P = 0.0004) as demonstrated by qRT-PCR analysis.
miR-375plasma levels were not predictive of
vandetanibresponse, 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-375as a promising prognostic marker for advanced MTC patients, to be validated in larger cohorts.
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