Friedrich Carsten, Shalaby Tarek, Oehler Christoph, Pruschy Martin, Seifert Burkhardt, Picard Daniel, Remke Marc, Warmuth-Metz Monika, Kortmann Rolf-Dieter, Rutkowski Stefan, Grotzer Michael A, von Bueren André O
Division of Pediatric Oncology and Hematology, University Children's Hospital Rostock, Ernst-Heydemann-Str. 8, 18057, Rostock, Germany.
Division of Pediatric Oncology, Hematology and Hemostaseology, Department of Women's and Children's Health, University Hospital Leipzig, Leipzig, Germany.
Childs Nerv Syst. 2017 Sep;33(9):1463-1471. doi: 10.1007/s00381-017-3506-y. Epub 2017 Jul 10.
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.
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.
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.
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.
原肌球蛋白受体激酶C基因（TrkC）的高信使核糖核酸（mRNA）表达与髓母细胞瘤患者的良好生存相关。目前尚未测试它是否通过调节对治疗的反应发挥作用，或者它是否可能是一个良好分子亚组的替代标志物。
将髓母细胞瘤来源的细胞系DAOY稳定转染以过表达TrkC（克隆DAOY-TrkC），并与对照（克隆DAOY-EV，转染空载体）进行比较。在照射或用化疗药物孵育后测试细胞活力（MTS试验）。在连续试验HIT'91/HIT2000中，将3至21岁术后有残留疾病的髓母细胞瘤患者术后化疗或全脑脊髓照射（CSI）的神经放射学反应与其肿瘤样本中的TrkC mRNA表达进行比较。根据分子亚组分析了五项特征明确的独立表达谱研究，共涵盖686例髓母细胞瘤患者的TrkC水平。
与DAOY-EV相比，DAOY-TrkC在暴露于递增剂量的照射、顺铂、依托泊苷或长春新碱后细胞活力无差异。虽然术后CSI无反应者（n = 5/19）的TrkC mRNA表达往往更高（p = 0.03，比值15.5，95%可信区间9-267），化疗有反应者（n = 23/43）也是如此（p = 0.04，比值6.1，95%可信区间1.1-35），两者均采用曼-惠特尼U检验分析（经Bonferroni校正后无显著性差异）。在所有表达谱研究中，SHH亚组中TrkC mRNA水平最高。
高TrkC mRNA表达在SHH亚组中似乎很常见，且似乎对髓母细胞瘤患者的治疗反应性没有重大影响。
