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

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 preamplified qRT-PCR methodology, we quantified miR-371a-3p levels in serum and cerebrospinal fluid (CSF) in a series of 4 representative clinical cases, 3 with intracranial malignant GCT and 1 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 (1) the only confirmatory evidence of an intracranial malignant GCT in 1 case, supporting clinical decision making; (2) early detection of intracranial malignant GCT in another, where an elevated CSF miR-371a-3p level preceded the histologically confirmed diagnosis by 2 years; and (3) 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 noninvasive 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.

Liquid Biopsies in the Clinical Management of Germ Cell Tumor Patients: State-of-the-Art and Future Directions

“…Other have demonstrated that these microRNAs could be detected in other bodily fluids apart from blood derivatives (malignant pleural effusions, seminal plasma, hydrocele fluid, cerebral spinal fluid), which gave further information about these biomarkers [ 67 , 83 , 98 ]. The evidence of stability in other fluids argues in favor of their use, for instance, in a metastatic context and in extragonadal GCTs, which was further confirmed [ 99 , 100 ]. These microRNAs were not detected in urine and studies in seminal plasma disclosed issues hampering the use of this bodily fluid for the diagnosis of TGCTs because of higher levels in the healthy control population compared to those observed in serum [ 83 , 101 , 102 , 103 ].…”

Molecular Pathology and Targeted Therapies for Personalized Management of Central Nervous System Germinoma

“…GCT are associated with up-regulation of the miR-371~373 and miR-302 clusters, disregarding tumour site, age, or histopathologic type [ 96 ]. MiR-371a-3p was identified as a reliable marker in the differential diagnosis between germinoma and Langerhans cell histiocytosis, granting an early detection in cases where imaging studies and serum/CSF work-up are inconclusive [ 97 ]. A prospective observational cohort study is currently recruiting patients to evaluate whether miRNA 371 can be used as a prognostic marker for the risk of GCT recurrence [ 98 ].…”

Vinblastine monotherapy induction prior to radiotherapy for patients with intracranial germinoma during the COVID‐19 pandemic

“…Carboplatin monotherapy, at modest dosing, has also been successfully utilized in intracranial germinoma to allow a reduction in subsequent radiotherapy doses 19 . Furthermore, we recently reported successful vinblastine monotherapy induction, prior to radiotherapy, in a patient with intracranial germinoma 20 . The patient presented with complete loss of vision, and imaging demonstrated a suprasellar lesion, measuring 36 × 28 × 23 mm.…”

“…Vision returned within 4 days of starting vinblastine and after further review, the diagnosis was revised to germinoma. After dramatic radiological reduction in tumor size after just two vinblastine doses (to 21 × 19 × 12 mm; a 77% volume reduction), a 12‐week induction course was delivered, with excellent response, prior to radiotherapy 20 . Importantly, both carboplatin and vinblastine schedules can be successfully delivered peripherally without recourse to placement of a central venous access device.…”

“…Due to the COVID‐19 pandemic, adapted UK guidelines for GCT patient management were distributed to clinicians, including potential nonstandard treatment options that would reduce hospital visits and/or admissions. This included vinblastine monotherapy as an option for intracranial germinoma, based on our case report 20 and practical/pragmatic considerations. We describe two patients successfully treated using this approach.…”