One of the most noteworthy input in the field of testicular cancer in the last decade has been the discovery and validation of specific microRNAs (e.g. miR-371a-3p) as accurate molecular biomarkers. The microRNA-based markers in fact outperform the classical markers used in routine. An overall critical assessment of the microRNA-based test clearly demonstrates its usefulness in several settings, from diagnosis to estimation of tumor burden, follow-up, and detection of relapses. Evidence has accumulated from 2006 where Voorhoeve et al.1 uncovered miR-372 and miR-373 (part of the miR-371-373 cluster) as oncogenic in testicular germ cell tumors. Since then many authors have been actively involved in studies building evidence on the pathobiological as well as the clinical relevance of these microRNAs, particularly of miR-371a-3p.
The experience of the Dutch, Danish, and German Groups, along with a critical review of current challenges, is given in this review. Overall, microRNAs have proved to be more informative than the combination of classical serum tumor biomarkers AFP and hCG (and LDH) in large retrospective and also prospective multicentric studies.
The miR-371a-3p stands out by its excellent diagnostic performance, with sensitivity and specificity over 90% for the initial diagnosis of a malignant testicular germ cell tumors and is based on a simple blood sample (serum or plasma). Detection of microRNAs is performed by regular real-time quantitative polymerase chain reaction (RT-qPCR) in a cost-effective manner. Other body fluids, such as cerebral spinal fluid and pleural effusion, can also be used for diagnosis and stress the ability to detect germ cell tumors in other topographies (either metastases or primary extragonadal malignancies).
Relative levels of microRNAs were also shown to relate to tumor burden and, importantly, they have been shown to decrease after surgical or systemic treatment (with a short half-life of fewer than 12 hours), and elevations were demonstrated to accurately signal disease relapse or viable disease in post-chemotherapy metastatic residual masses, where the classical markers again often show limited value.
All this evidence is currently pushing the miR-371a-3p closer to introduction in the clinic, but still, some challenges persist; one of the biggest drawbacks of these embryonic microRNAs is the lack of detection of the (fully differentiated) mature teratoma subtype, for which classical markers are also not informative. Also, the microRNAs are not able to detect (with enough sensitivity) patients harboring only the precursor lesion, germ cell neoplasia in situ (GCNIS). Lastly, before this biomarker can be fully introduced in the clinic, an effort for standardizing pre-analytical steps and methodologies must be made.
In conclusion, miR-371a-3p deserves to be further evaluated in well-designed multi-center studies to prove its actual clinical impact.
Written by: Kristian Almstrup, João Lobo, Nina Mørup, Gazanfer Belge, Ewa Rajpert-De Meyts, Leendert H J Looijenga, Klaus-Peter Dieckmann
Department of Growth and Reproduction, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark., Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto) & Porto Comprehensive Cancer Center (P.CCC), R. Dr. António Bernardino de Almeida, Porto, Portugal., Department of Growth and Reproduction, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark., University Bremen, Faculty of Biology & Chemistry, Bremen, Germany., Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands., Department of Urology, Hodentumorzentrum Hamburg, Asklepios Klinik Altona, Hamburg, Germany.
- Voorhoeve, P. Mathijs, Carlos Le Sage, Mariette Schrier, Ad JM Gillis, Hans Stoop, Remco Nagel, Ying-Poi Liu et al. "A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors." Cell 124, no. 6 (2006): 1169-1181.