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Application of miRNAs in the diagnosis and monitoring of testicular germ cell tumours

Nature Reviews Urology volume 17, pages 201–213 (2020)Cite this article

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Abstract

Testicular germ cell tumours (TGCTs) are the most frequent cancer type in young men and originate from the common precursor germ cell neoplasia in situ (GCNIS). For decades, clinical management of patients with TGCT has relied on classic serum tumour markers: α-fetoprotein, human chorionic gonadotropin subunit-β and lactate dehydrogenase. In the past 10 years, microRNAs have been shown to outperform classic serum tumour markers in the diagnosis of primary tumours and in follow-up monitoring and prediction of relapse. miR-371a-3p is the most consistent marker and exhibits >90% diagnostic sensitivity and specificity in TGCT. However, miR-371a-3p cannot be used to diagnose GCNIS or mature teratoma. Future efforts must technically standardize the microRNA-based methods internationally and introduce miR-371a-3p as a molecular liquid biopsy-based marker for TGCTs in the clinic.

Key points

  • The currently available protein-based serum markers of testicular germ cell tumours (TGCTs), α-fetoprotein (AFP), human chorionic gonadotropin subunit-β (β-HCG) and lactate dehydrogenase (LDH), show poor diagnostic performance, especially for seminomas.

  • New microRNA-based biomarkers, particularly miR-371a-3p, outperform the existing protein-based serum markers in diagnostic performance and enable detection of seminomas.

  • Validated miRNA-based tests can change clinical decision-making in the primary diagnosis and follow-up monitoring of patients with TGCT.

  • Introducing miRNA-based biomarker testing reduces the costs of patient monitoring by reducing the number of imaging scans needed in patients with negative results.

  • Novel biomarkers are needed to overcome the limitations of miR-371a-3p, such as in the diagnosis of mature teratoma and of the precursor lesion, germ cell neoplasia in situ.

  • Universal standardization of protocols is needed for detecting, quantifying and reporting miRNA-based biomarkers in patients with TGCT.

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Fig. 1: Developmental biology as a driver for uncovering testicular germ cell tumour biomarkers.
Fig. 2: Sensitivity of the classic serum tumour markers AFP, β-HCG and LDH in detecting TGCT compared with miRNA-based markers (all miRNA tests considered).

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Acknowledgements

The authors receive funding from Innovation Fund Denmark and the Børnecancerfonden (grant numbers 14-2013-4 and 2016-0304 to K.A., N.M. and E.R.-De M.); ReproUnion and the Svend Andersen Foundation (no grant numbers, to K.A. and N.M.); FCT (Fundação para a Ciência e Tecnologia; grant numbers POCI-01-0145-FEDER-29043 and SFRH/BD/132751/2017 to J.L.); and Deutsche Krebshilfe (grant number 70113186 to G.B. and K.-P.D.).

Review criteria

We performed a review of PubMed (2019), using the search terms of “germ cell cancer” or “germ cell tumour”, “miRNA” and “plasma” and focused on papers relating to diagnostics (Table 1). Studies were reviewed according to the Standards for Reporting Diagnostic Accuracy Studies (STARD) guidelines: https://www.equator-network.org/reporting-guidelines/stard/.

Author information

Author notes

  1. These authors contributed equally to this work: Kristian Almstrup, João Lobo.

  2. These authors jointly supervised this work: Leendert H. J. Looijenga, Klaus-Peter Dieckmann.

Authors and Affiliations

  1. Department of Growth and Reproduction, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Kristian Almstrup, Nina Mørup & Ewa Rajpert-De Meyts

  2. International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Kristian Almstrup, Nina Mørup & Ewa Rajpert-De Meyts

  3. 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

    João Lobo

  4. Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands

    João Lobo & Leendert H. J. Looijenga

  5. University Bremen, Faculty of Biology & Chemistry, Bremen, Germany

    Gazanfer Belge

  6. Department of Urology, Hodentumorzentrum Hamburg, Asklepios Klinik Altona, Hamburg, Germany

    Klaus-Peter Dieckmann

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Contributions

K.A., J.L., N.M., E.R.-De M., L.H.J.L. and K.-P.D. researched data for and wrote the manuscript. All authors made substantial contributions to discussion of the content and reviewed and edited the manuscript before submission.

Corresponding authors

Correspondence to Kristian Almstrup, Leendert H. J. Looijenga or Klaus-Peter Dieckmann.

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Competing interests

K.-P.D. and G.B. each possess 9.7% ownership shares in miRdetect GmbH, Bremen. All remaining authors declare no competing interests.

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Nature Reviews Urology thanks D. Nettersheim, R. Huddart and P. Giannatempo for their contribution to the peer review of this work.

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Glossary

Germ cell neoplasia in situ

(GCNIS). The pre-invasive lesion from which type II testicular germ cell tumours (seminomas and non-seminomas) derive.

Cryptorchidism

A condition in which the testes have not descended into the scrotum.

Disorders of sex development

Conditions in which the gonads and genitalia have not developed as expected, sometimes resulting in gender ambiguity or even a gender opposite to that determined by genetics.

Testicular dysgenesis syndrome

A syndrome that is caused by poor gonadal development in fetal life and later manifests as either poor semen quality, cryptorchidism, some forms of hypospadias or testicular germ cell cancer.

Sex-determination

The process of gonadal development into either testes or ovaries.

Seminomas

Morphologically homogeneous subtype of testicular germ cell tumours derived from germ cell neoplasia in situ.

Non-seminomas

Heterogeneous subtype of testicular germ cell tumours that can be composed of embryonal carcinoma, teratoma, yolk sac tumour and choriocarcinoma.

Orchiectomy

Surgical removal of a testis.

Liquid biopsies

Analyses of body fluids, most commonly a blood sample, for biomarkers that can diagnose a disease or condition.

miRNAs

Small molecules of RNA that are 21–24 bases long.

Classic serum tumour markers

Protein-based biomarkers in serum commonly used for managing patients with testicular germ cell tumours. They include α-fetoprotein (AFP), human chorionic gonadotropin subunit-β (β-HCG), and lactate dehydrogenase (LDH).

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Almstrup, K., Lobo, J., Mørup, N. et al. Application of miRNAs in the diagnosis and monitoring of testicular germ cell tumours. Nat Rev Urol 17, 201–213 (2020). https://doi.org/10.1038/s41585-020-0296-x

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