MicroRNA-371a-3p-The Novel Serum Biomarker in Testicular Germ Cell Tumors

Abstract

Introduction: Testicular germ cell tumors (TGCTs) are a paradigm for the use of serum tumor markers in clinical management. However, conventional markers such as alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (hCG), and lactate dehydrogenase (LDH) have quite limited sensitivities and specificities. Within the last decade, the microRNA-371a-3p (miR371) emerged as a possible new biomarker with promising features.

Areas covered: This review covers the typical features as well as possible clinical applications of miR371 in TGCT patients, such as initial diagnosis, therapy monitoring, and follow-up. Additionally, technical issues are discussed.

Expert opinion: With a sensitivity of around 90% and specificity >90%, miR371 clearly outperforms the classical serum tumor markers in TGCTs. The unique features of the test involve the potential of modifying recent standards of care in TGCT. In particular, miR371 is expected to aid clinical decision-making in scenarios such as discriminating small testicular TGCT masses from benign ones prior to surgery, assessing equivocal lymphadenopathies, and monitoring chemotherapy results. Likewise, it is expected to make follow-up easier by reducing the intensity of examinations and by sparing imaging procedures. Overall, the data presently available are promising, but further prospective studies are required before the test can be implemented in standard clinical care.

Keywords: MicroRNA; biomarker; germ cell tumor; miRNA; testicular cancer.

Figure 1

Typical example of an incidentally detected small testicular mass. Sonographic image of left testis showing an 8 mm hypo-echoic mass in the caudal pole region with testicular perfusion visualized by doppler sonography in red and blue. Surgery revealed pure seminoma; miR371 was slightly elevated preoperatively, so inguinal orchiectomy was performed without frozen section examination.

Figure 2

Receiver operating characteristics curve (ROC) showing sensitivity and specificity of miR371 for the primary diagnosis of testicular germ cell tumors (TGCT). The data used in this analysis (420 TGCT patients and 230 healthy controls) are derived from an interim analysis of the study of the German Testicular Cancer Study Group, the final results of which were published later [32]. The area under the curve (AUC) of 0.967 is close to the ideal goal of 1.0. The sensitivity and specificity calculated from these data amount to 89.8% and 93.6%, respectively.

Figure 3

Box and whisker diagram showing the median serum level of miR371 in 230 healthy controls and in 298 clinical stage I (cSI) patients before and after orchiectomy. The data used in this analysis are derived from an interim analysis of the study of the German Testicular Cancer Study Group, the final results of which were published later [34]. There is a significant drop of the median miR level subsequent to orchiectomy; however, 20% of cases do not decrease to normal. This analysis formed the basis for the hypothesis that incomplete decreases after orchiectomy might indicate patients at increased risk of progression. * denotes outliers.

Figure 4

Box plot diagram showing median miR371 levels in patients with clinical stages 2 (n = 69) and cS3 (n = 23) before and after each cycle of chemotherapy. The data used in this analysis are derived from an interim analysis of the study of the German Testicular Cancer Study Group, the final results of which were published later [34]. There is a significant drop in median levels of both cS2 and cS3 patients after the first cycle of chemotherapy. Further decrease is only observed in cS3 patients (blue line), green line denotes cS2 patients. Dots represent outliers. The star in the right upper corner (arrow) denotes one patient not responding to chemotherapy. The graph illustrates that miR levels correlate with the amount of vital tumor bulk.

Figure 5

Cross-section of a surgical specimen from the postchemotherapy retroperitoneal lymph node dissection of a residual mass in a patient with metastasized nonseminoma showing the typical macroscopic feature of pure teratoma. This histologic subtype does not express miR371.