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Tropomyosin receptor kinase C (TrkC) expression in medulloblastoma: relation to the molecular subgroups and impact on treatment response

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Abstract

Purpose

High messenger RNA (mRNA) expression of the tropomyosin receptor kinase C gene (TrkC) has been associated with favorable survival in medulloblastoma patients. Untested is whether it plays a role through modulating the response to therapy or whether it might be a surrogate marker for a favorable molecular subgroup.

Methods

The medulloblastoma-derived cell line DAOY was stably transfected to overexpress TrkC (clone DAOY-TrkC) and compared to a control (clone DAOY-EV, empty vector transfected). Cell viability (MTS assay) was tested after irradiation or incubation with chemotherapeutic drugs. Neuroradiologic response to postoperative chemotherapy or craniospinal irradiation (CSI) of medulloblastoma patients aged 3–21 years with postoperative residual disease treated within the consecutive trials HIT’91/HIT2000 was compared to TrkC mRNA expression in their tumor samples. Five well-characterized independent expression-profiling studies covering together 686 medulloblastoma patients were analyzed for TrkC levels according to the molecular subgroups.

Results

Cell viability of DAOY-TrkC compared to DAOY-EV was not different after exposure to increasing doses of irradiation, cisplatin, etoposide, or vincristine. While TrkC mRNA expression tended to be higher in non-responders (n = 5/19) to postoperative CSI (p = 0.03, ratio 15.5, 95% CI 9–267), this was the case in responders (n = 23/43) to chemotherapy (p = 0.04, ratio 6.1, 95% CI 1.1–35), both analyzed with Mann–Whitney U test (not significant after Bonferroni adjustment). The highest TrkC mRNA levels were found in the SHH subgroup across all expression-profiling studies.

Conclusions

High TrkC mRNA expression appears to be frequent in the SHH subgroup and seems not to have a major effect on therapy responsiveness in medulloblastoma patients.

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Acknowledgements

This work was supported by the Swiss National Funds (32-104203/1), the Swiss Research Foundation Child and Cancer, and the German Children’s Cancer Foundation (Deutsche Kinderkrebsstiftung). We would like to thank the CANSEARCH Foundation for continuous support. We thank Dr. Luciano Molinari (University Children’s Hospital of Zurich, Switzerland) for helpful discussions regarding statistical analysis. We would like to thank Wiebke Treulieb and Christine Lindow (HIT data center) for their excellent data management.

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Authors and Affiliations

  1. Division of Pediatric Oncology and Hematology, University Children’s Hospital Rostock, Ernst-Heydemann-Str. 8, 18057, Rostock, Germany

    Carsten Friedrich

  2. Division of Pediatric Oncology, Hematology and Hemostaseology, Department of Women’s and Children’s Health, University Hospital Leipzig, Leipzig, Germany

    Carsten Friedrich

  3. Department of Oncology, University Children’s Hospital, Zürich, Switzerland

    Tarek Shalaby & Michael A. Grotzer

  4. Department of Radiation Oncology, University Hospital Zürich, Zurich, Switzerland

    Christoph Oehler

  5. Department of Radiation Oncology, Hospital Graubünden, Chur, Switzerland

    Christoph Oehler

  6. Laboratory for Molecular Radiobiology, Radiation Oncology, University Hospital Zürich, Zürich, Switzerland

    Martin Pruschy

  7. Department of Biostatistics, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland

    Burkhardt Seifert

  8. Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Düsseldorf, Germany

    Daniel Picard & Marc Remke

  9. Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany

    Daniel Picard & Marc Remke

  10. Department of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany

    Daniel Picard & Marc Remke

  11. Department of Neuroradiology, University of Würzburg, Würzburg, Germany

    Monika Warmuth-Metz

  12. Department of Radiation Oncology, University of Leipzig, Leipzig, Germany

    Rolf-Dieter Kortmann

  13. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Stefan Rutkowski & André O. von Bueren

  14. Department of Pediatrics, Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany

    André O. von Bueren

  15. Division of Pediatric Hematology and Oncology, University Hospital of Geneva, Geneva, Switzerland

    André O. von Bueren

  16. Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland

    André O. von Bueren

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  1. Carsten Friedrich
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  2. Tarek Shalaby
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Correspondence to Carsten Friedrich.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

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Friedrich, C., Shalaby, T., Oehler, C. et al. Tropomyosin receptor kinase C (TrkC) expression in medulloblastoma: relation to the molecular subgroups and impact on treatment response. Childs Nerv Syst 33, 1463–1471 (2017). https://doi.org/10.1007/s00381-017-3506-y

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