Carsten Friedrich1,2, Tarek Shalaby3, Christoph Oehler4,5, Martin Pruschy6, Burkhardt Seifert7, Daniel Picard8,9,10, Marc Remke8,9,10, Monika Warmuth-Metz11, Rolf-Dieter Kortmann12, Stefan Rutkowski13, Michael A Grotzer3, André O von Bueren13,14,15,16. 1. Division of Pediatric Oncology and Hematology, University Children's Hospital Rostock, Ernst-Heydemann-Str. 8, 18057, Rostock, Germany. contact.cfriedri@gmail.com. 2. Division of Pediatric Oncology, Hematology and Hemostaseology, Department of Women's and Children's Health, University Hospital Leipzig, Leipzig, Germany. contact.cfriedri@gmail.com. 3. Department of Oncology, University Children's Hospital, Zürich, Switzerland. 4. Department of Radiation Oncology, University Hospital Zürich, Zurich, Switzerland. 5. Department of Radiation Oncology, Hospital Graubünden, Chur, Switzerland. 6. Laboratory for Molecular Radiobiology, Radiation Oncology, University Hospital Zürich, Zürich, Switzerland. 7. Department of Biostatistics, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland. 8. Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Düsseldorf, Germany. 9. Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany. 10. Department of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany. 11. Department of Neuroradiology, University of Würzburg, Würzburg, Germany. 12. Department of Radiation Oncology, University of Leipzig, Leipzig, Germany. 13. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 14. Department of Pediatrics, Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany. 15. Division of Pediatric Hematology and Oncology, University Hospital of Geneva, Geneva, Switzerland. 16. Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
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.
PURPOSE: High messenger RNA (mRNA) expression of the tropomyosin receptor kinase C gene (TrkC) has been associated with favorable survival in medulloblastomapatients. 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 medulloblastomapatients 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 medulloblastomapatients 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 medulloblastomapatients.
Entities:
Keywords:
Molecular marker; Molecular subgroups; Response to therapy
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