Developing a Highly Specific Biomarker for Germ Cell Malignancies: Plasma miR371 Expression Across the Germ Cell Malignancy Spectrum

Abstract

PURPOSE Our objective was to evaluate operating characteristics, particularly specificity and positive predictive value (PPV), by mapping plasma miR371 expression to actual clinical events in patients with a history of germ cell tumor. PATIENTS AND METHODS One hundred eleven male patients with a history of or newly diagnosed germ cell tumors were evaluable. Biospecimens obtained before confirmed clinical events were analyzed for miR371 expression with blinding of providers and laboratory personnel to analytic results or clinical status, respectively. Cases (patients with clinically confirmed active germ cell malignancy [aGCM]) and controls (patients with no clinically confirmed aGCM) were assigned over the course of the management. Patients were assigned risk status (high, low, or moderate) based on the composite clinical picture at time points in management. RESULTS Considering all cases and controls and results of prospectively obtained biosamples analyzed for miR371 expression, 46 (35%) of 132 samples had clinically confirmed aGCM over the course of management; 44 (96%) of these 46 patients had plasma miR371 expression (true positives) with no false positives. Two (4%) of 46 patients had no miRNA expression despite pathologic confirmation of aGCM (false negatives). Plasma miR371 expression in confirmed aGCM had a specificity, sensitivity, positive predictive value, and negative predictive value of 100%, 96%, 100%, and 98%, respectively. Interpretation of sensitivity and negative predictive value is limited by modest follow-up. Specificity and sensitivity were 100% and 98%, 100% and 92%, and 100% and 97% in the low-, moderate-, and high-risk groups, respectively, with a median follow-up time of 15 months. CONCLUSION Plasma miR371 expression predicts aGCM with high specificity and positive predictive value. Although other operating characteristics of miR371 await longer follow-up for more complete definition, the findings of a highly specific liquid biopsy strongly support moving forward with large-scale, real-world clinical trials to further define full operating characteristics and to identify clinical utility and areas of patient benefit.

Graded expression of microRNA-371a-3p in tumor tissues, contralateral testes, and in serum of patients with testicular germ cell tumor

“…Of the candidate miRs, miR-371a-3p appears to be the most promising serum marker of GCT with a sensitivity of 90.1% and specificity of 94.1% [4,5] outperforming the classical markers (alpha fetoprotein, beta human chorionic gonadotropin, lactate dehydrogenase) with their sensitivities of less than 50% [6]. Apparently, miR-371a-3p features almost all of the qualities a valuable tumor marker is supposed to have [7] since it correlates with clinical stages, and tumor sizes, it highlights response (or non-response) to therapy, and it is present in cases with relapsing GCT suggesting a prominent role of this miR upon follow-up examinations [8][9][10][11][12][13][14][15]. Preliminary data also suggest a possible role of the test upon evaluation of residual masses after chemotherapy [13,16,17].…”

High Expression of microRNA-371a-3p in Cystic Fluid of Post-Chemotherapy Teratoma with Concurrent Normal Serum Levels in Patients with Non-Seminomatous Testicular Germ Cell Tumours

“…After the discovery of circulating miR-371 in the serum of GCT patients, the miR has been detected in a variety of other body fluids, such as plasma, testicular vein blood, tumour-surrounding hydrocele fluid, cerebrospinal fluid of patients with intracranial GCT, pleural effusion, seminal plasma, and ejaculate fluid, but not in urine [18, 20, 24-27]. The documentation of miR-371 in the fluid of teratomatous cysts adds, therefore, one further body fluid to the list of compartments where expression of the miR is found, thus enhancing our understanding of the biology of both miR-371 and GCT.…”

Seminoma presenting as a solitary metastasis in gastric mucosa with regressed testicular mass

“…So far, serologic tumor markers for germ cell tumors’ diagnosis and monitoring have limited value in the diagnosis of pure seminomas. Recent studies have focused on miRNA clusters, identifying miR371 as a potential new serum biomarker, and the plasma miR371 expression predicts GCT with high specificity and positive predictive value 5 …”