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The present and future of serum diagnostic tests for testicular germ cell tumours

Nature Reviews Urology volume 13, pages 715–725 (2016)Cite this article

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Key Points

  • The conventional serum protein tumour markers α-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and lactate dehydrogenase (LDH) show utility in the management of testicular malignant germ cell tumours (GCTs)

  • AFP and hCG show limited sensitivity and specificity for all malignant GCTs, being representative of yolk sac tumour and choriocarcinoma or synctiotrophoblast subtypes, respectively; LDH is a very nonspecific biomarker

  • Novel universal biomarkers for testicular malignant GCTs are required, particularly for seminoma and embryonal carcinoma subtypes that are typically negative for conventional markers

  • MicroRNAs are short, non-protein-coding RNAs that show much promise as universal markers in malignant GCTs

  • Individual microRNAs from two microRNA clusters, miR-371–373 and miR-302–367, are overexpressed in all malignant GCTs, regardless of patient age, tumour site and subtype

  • A panel of four circulating microRNAs from these two clusters (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p) is highly sensitive and specific for the diagnosis of malignant GCT, including seminoma and embryonal carcinoma subtypes

  • Practical considerations need to be addressed to standardize the translation of circulating microRNA studies from a research tool to a routine clinical test

Abstract

Testicular germ cell tumours (GCTs) are the most common malignancy occurring in young adult men and the incidence of these tumours is increasing. Current research priorities in this field include improving overall survival for patients classified as being 'poor-risk' and reducing late effects of treatment for patients classified as 'good-risk'. Testicular GCTs are broadly classified into seminomas and nonseminomatous GCTs (NSGCTs). The conventional serum protein tumour markers α-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and lactate dehydrogenase (LDH) show some utility in the management of testicular malignant GCT. However, AFP and hCG display limited sensitivity and specificity, being indicative of yolk sac tumour (AFP) and choriocarcinoma or syncytiotrophoblast (hCG) subtypes. Furthermore, LDH is a very nonspecific biomarker. Consequently, seminomas and NSGCTs comprising a pure embryonal carcinoma subtype are generally negative for these conventional markers. As a result, novel universal biomarkers for testicular malignant GCTs are required. MicroRNAs are short, non-protein-coding RNAs that show much general promise as biomarkers. MicroRNAs from two 'clusters', miR-371–373 and miR-302–367, are overexpressed in all malignant GCTs, regardless of age (adult or paediatric), site (gonadal or extragonadal) and subtype (seminomas, yolk sac tumours or embryonal carcinomas). A panel of four circulating microRNAs from these two clusters (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p) is highly sensitive and specific for the diagnosis of malignant GCT, including seminoma and embryonal carcinoma. In the future, circulating microRNAs might be useful in diagnosis, disease monitoring and prognostication of malignant testicular GCTs, which might also reduce reliance on serial CT scanning. For translation into clinical practice, important practical considerations now need addressing.

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Figure 1: Differential expression of the microRNAs (miR)-371–373 and miR-302–367 clusters in malignant germ cell tumours (GCT).
Figure 2: A proposed pipeline for quantification of circulating microRNAs (miRs) in malignant germ cell tumours (GCTs)12.

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Acknowledgements

The authors would like to acknowledge grant funding from CwCUK/GOSHCC (grant W1058 to M.J.M. and N.C.), SPARKS (grant 11CAM01 to M.J.M. and N.C.), CRUK (grant A13080 to N.C.) MRC (grant MC_EX_G0800464 to M.J.M.) and National Health Service funding to the Royal Marsden/Institute of Cancer Research National Institute for Health Research Biomedical Research Centre for Cancer (R.A.H.). The authors also thank the Max Williamson Fund, the Josh Carrick Foundation and The Perse Preparatory School, Cambridge for support.

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Authors and Affiliations

  1. Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK

    Matthew J. Murray & Nicholas Coleman

  2. Department of Paediatric Haematology and Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK

    Matthew J. Murray

  3. The Institute of Cancer Research, Downs Road, Sutton, SM2 5PT, Surrey, UK

    Robert A. Huddart

  4. The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, SM2 5PT, Surrey, UK

    Robert A. Huddart

  5. Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK

    Nicholas Coleman

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All authors researched data for the article, made a substantial contribution to discussions of content, wrote and edited the manuscript before submission.

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M.J.M. and N.C. receive laboratory funding from AstraZeneca as part of a collaborative research programme investigating clinical applications of circulating microRNA quantification. R.A.H. declares no competing interests.

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Murray, M., Huddart, R. & Coleman, N. The present and future of serum diagnostic tests for testicular germ cell tumours. Nat Rev Urol 13, 715–725 (2016). https://doi.org/10.1038/nrurol.2016.170

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