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Clinical utility of circulating miR-371a-3p for the management of patients with intracranial malignant germ cell tumors.

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Abstract Background. The current biomarkers alpha-fetoprotein (AFP) and human-chorionic-gonadotropin (HCG) have limited sensitivity/specificity for diagnosing malignant germ-cell-tumors (GCTs) and ‘marker-negative’ patients require histological confirmation for diagnosis. However, GCTs at intracranial sites are surgically relatively inaccessible and biopsy carries risks. MicroRNAs from the miR-371~373 and miR-302/367 clusters are over-expressed in all malignant GCTs and, in particular, miR-371a-3p shows elevated serum levels at diagnosis for testicular disease. Methods. Using our robust pre-amplified qRT-PCR methodology, we quantified miR-371a-3p levels in serum and cerebrospinal fluid (CSF) in a series of four representative clinical cases, three with intracranial malignant GCT and one with Langerhans cell histiocytosis (LCH), compared with appropriate control cases. Results. Serum and/or CSF miR-371a-3p levels distinguished those with intracranial malignant GCTs from LCH and, if known in real-time, could have helped clinical management. The benefits would have included: i) the only confirmatory evidence of an intracranial malignant GCT in one case, supporting clinical decision-making; ii) early detection of intracranial malignant GCT in another, where an elevated CSF miR-371a-3p level preceded the histologically-confirmed diagnosis by two years, and iii) confirmation of an intracranial malignant GCT relapse with an elevated serum miR-371a-3p level, where serum and CSF AFP and HCG levels were below thresholds for such a diagnosis. Conclusions. This series highlights the potential for microRNA quantification to assist the non-invasive diagnosis, prognostication and management for patients with intracranial malignant GCTs. Serum and CSF should be collected routinely as part of future studies to facilitate the extension of these findings to larger patient cohorts.



biomarker, germ cell tumor, miR-371a-3p, microRNA, vinblastine

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NeuroOncology Advances

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Oxford University Press
Isaac Newton Trust (1540 (f))
St Baldrick's Foundation (via Dana-Farber Cancer Institute) (2015-0743)
Addenbrooke's Charitable Trust (ACT) (minute 23/17 B (iv))
The authors acknowledge grant funding from the St. Baldrick’s Foundation [reference 358099], the Isaac Newton Trust [reference 15.40f] and Addenbrooke’s Charitable Trust [reference 23/17 B (iv)]. We are grateful for support from the Max Williamson Fund and from Christiane and Alan Hodson, in memory of their daughter Olivia.