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

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 ( = 20), including matched plasma/tissue samples ( = 17/20), and a validation cohort, yielding only plasma samples ( = 17). Plasma samples from healthy subjects ( = 36) and MTC patients in remission ( = 9) were used as controls. MTC ( = 17 from 8 patients included in discovery cohort) and non-neoplastic thyroid specimens ( = 3) were assessed by microarray profiling to identify candidate circulating miRNAs. qRT-PCR and 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 ( < 0.0001) and subjects in remission ( = 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, < 0.0001) and were a strong prognostic factor of poor prognosis (HR 6.24, = 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.

CircHN1 affects cell proliferation and migration in gastric cancer

“…MiR‐375 plays a dual role in the development and progression of cancer. It acts as an oncomiR in some cancers 29,30 but as a tumor suppressor miRNA in the others 31,32 . A high frequency of recurrence and poor survival is observed in GC patients with high level of miR‐375 33 .…”

The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: A systematic review

“…The majority investigated the clinical role of somatic RET mutations 8,10-20 ; however, four included somatic RAS mutations 12,13,21,22 and one focussed on somatic CDKN2C mutations. 23 Six studies utilized tumour miRNA expression, 9,21,[24][25][26][27] two focussed on tumour methylation levels 28,29 and one on tumour mTOR expression. 30 The general characteristics of included studies are represented in Table 1.…”

Role of tissue and circulating microRNAs and DNA as biomarkers in medullary thyroid cancer

“…This leads to clinicians missing an important window of opportunity where patients could be treated before recurrence is established. In this context, reliable detection of progressive disease (PD) with novel non-invasive biomarkers is crucial in order to obtain prognosis stratification, differentiation of aggressive MTCs from indolent ones and evaluate TKI therapy effectiveness (Romeo, et al, 2018). MicroRNAs (miRNAs) are 18-25 nucleotide long non-coding RNAs that act as post-transcriptional regulators of gene expression.…”

“…To date, there are only 3 studies investigating miRNA expression levels from MTC patients-derived plasma or serum samples, summarized in Table 3. Romeo et al identified high levels of circulating miR-375 in MTC respect to sex-and age-matched healthy controls and reported its correlation with distant metastases and reduced overall survival (OS) (Romeo, et al, 2018). Of note, plasma miR-375 levels failed to distinguish patients with partial response or stable disease respect to those with disease progression.…”