Neurotrophin Receptor TrkC Predicts Good Clinical Outcome in Medulloblastoma and Other Primitive Neuroectodermal Brain Tumors

Abstract.

Background: Neurotrophins and their cognate receptors TrkA, TrkB and TrkC regulate proliferation, differentiation and death of neuronal progenitor cells and may be implicated in the progression of medulloblastoma and other primitive neuroectodermal brain tumors (PNET). These common childhood brain tumors are composed of morphologically undifferentiated cells that have important similarities to neuroectodermal progenitor cells of the developing CNS. Patients and Methods: To identify biologic prognostic factors in childhood PNET we determined expression levels of TrkC mRNA in tumor samples from 87 PNET patients by in situ hybridization. Comparison of TrkC mRNA expression levels with clinical variables was performed using univariate and multivariable Cox regression analysis. Results: Cox regression analysis revealed that children with tumors expressing no or little TrkC mRNA had a 4.8-fold (p < 0.00005) greater risk of death than children with tumors with high TrkC mRNA expression. This hazard ratio remained consistent after adjusting for clinical variables. Five-year survival was 89 % for patients with PNETs expressing high levels of TrkC mRNA and 47 % for patients with PNETs expressing little or no levels of TrkC mRNA (log rank; p < 0.00005). Conclusions: The TrkC neurotrophin receptor appears to be a powerful independent prognostic factor in PNET and may have a role in patient assignment to risk-based treatment strategies.

Hintergrund: Neurotrophine und Neurotrophin-Rezeptoren TrkA, TrkB und TrkC regulieren Proliferation, Differenzierung und Tod von neuronalen Vorläuferzellen des ZNS und sind möglicherweise an der Progression von Medulloblastom und anderen primitiven neuroektodermalen Hirntumoren (PNET) beteiligt. Diese häufigen kindlichen Hirntumoren bestehen aus undifferenzierten Zellen, die Ähnlichkeiten haben zu neuroektodermalen Vorläuferzellen des sich entwickelnden Zentralen Nervensystems. Patienten und Methoden: Um biologische prognostische Faktoren für PNET zu identifizieren, haben wir TrkC-mRNA-Expression in Tumorproben von 87 PNET-Patienten mittels In-situ-Hybridisierung gemessen. Mittels univariater und multivariabler Cox-Regressionsanalyse haben wir TrkC-mRNA-Expression mit klinischen Variabeln verglichen. Ergebnisse: Cox-Regressionsanalyse ergab, dass Kinder deren Tumoren tiefe Werte von TrkC mRNA aufwiesen, ein 4,8fach (p < 0,00005) größeres Risiko aufwiesen, zu sterben, als Kinder deren Tumoren hohe TrkC-mRNA-Expression hatten. Die Hazard Ratio blieb signifikant nach Korrektur für klinische Variabeln. Die 5-Jahres-Überlebenswahrscheinlichkeit betrug 89 % für Patienten mit PNET hoher TrkC-mRNA-Expression und 47 % für Patienten mit PNET niedriger TrkC-mRNA-Expression (log rank; p < 0,00005). Schlussfolgerung: Der TrkC-Neurotrophin-Rezeptor scheint ein wichtiger unabhängiger Prognosefaktor für PNET zu sein und könnte eine wichtige Rolle bekommen in der risikoadaptierten Behandlung von Kindern mit PNET.

Key words:

Brain tumor - medulloblastoma - PNET - prognosis

Schlüsselwörter:

Hirntumor - Medulloblastom - PNET - Prognose

Literatur

• 01 Albright  A L, Wisoff  J H, Zeltzer  P M, Boyett  J M, Rorke  L B, Stanley  P. Effects of medulloblastoma resections on outcome in children: a report from the Children's Cancer Group.  Neurosurgery. 1996;  38 265-271
• 02 Barbacid  M. Nerve growth factor: a tale of two receptors.  Oncogene. 1993;  8 2033-2042
• 03 Chao  M V. Neurotrophin receptors: a window into neuronal differentiation.  Neuron. 1992;  9 583-593
• 04 Dennis  M, Spiegler  B J, Hetherington  C R, Greenberg  M L. Neuropsychological sequelae of the treatment of children with medulloblastoma.  J Neuro-Oncol. 1996;  29 91-101
• 05 Duffner  P K, Horowitz  M E, Krischer  J P, Friedman  H S, Burger  P C, Cohen  M E, Sanford  R A, Mulhern  R K, James  H E, Freeman  C R, Seidel  F G, Kun  L E. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors.  N Engl J Med. 1993;  328 1725-1731
• 06 Garton  G R, Schomberg  P J, Scheithauer  B W, Shaw  E G, Ilstrup  D M, Blackwell  C R, Laws  E R, Earle  J D. Medulloblastoma - prognostic factors and outcome of treatment: review of the Mayo clinic experience.  Mayo Clin Proc. 1990;  65 1077-1086
• 07 Grotzer  M A, Janss  A J, Fung  K-M, Biegel  J A, Sutton  L N, Rorke  L B, Zhao  H, Cnaan  A, Phillips  P C, Lee  V M-Y, Trojanowski  J Q. TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors.  J Clin Oncol. 2000;  18 1027-1035
• 08 Kim  J YH, Sutton  M E, Lu  D J, Cho  T A, Goumnerova  L C, Goritchenko  L, Kaufman  J R, Lam  K K, Billet  A L, Tarbell  N J, Wu  J, Allen  J C, Stiles  C D, Segal  R A, Pomeroy  S L. Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastoma.  Cancer Res. 1999;  59 711-719
• 09 Korsching  S. The neurotrophic factor concept: a reexamination.  J Neurosci. 1993;  13 2739-2748
• 10 Lindsay  R M, Wiegand  S J, Altar  C A, DiStefano  P S. Neurotrophic factors: from molecule to man.  Trends Neurosci. 1994;  17 182-190
• 11 Muragaki  Y, Chou  T T, Kaplan  D R, Trojanowski  J Q, Lee  V M. Nerve growth factor induces apoptosis in human medulloblastoma cell lines that express TrkA receptor.  J Neurosci. 1997;  17 530-542
• 12 Nakagawara  A, Arima-Nakagawara  M, Scavarda  N J, Azar  C G, Cantor  A B, Brodeur  G M. Association between hight levels of expression of the trk gene and favorable outcome in human neuroblastoma.  N Engl J Med. 1993;  328 847-854
• 13 Packer  R J, Sutton  L N, Elterman  R, Lange  B, Goldwein  J W, Nicholson  H S, Mulne  L, Boyett  J, D'Angio  G J, Wechsler-Jentzsch  K, Reaman  G, Cohen  B H, Bruce  D A, Rorke  L B, Molloy  P, Ryan  J, LaFond  D, Evans  A E, Schut  L. Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy.  J Neurosurg. 1994;  81 690-698
• 14 Pollack  I F. Brain tumors in children.  N Engl J Med. 1994;  331 1500-1507
• 15 Radcliffe  J, Packer  R J, Atkins  T E, Bunin  G R, Schut  L, Goldwein  J W, Sutton  L N. Three- and four-year cognitive outcome in children with noncortical brain tumors treated with whole-brain radiotherapy.  Ann Neurol. 1992;  32 551-554
• 16 Segal  R A, Goumnerova  L C, Kwon  Y K, Stiles  C D, Pomeroy  S L. Expression of the neurotrophin receptor trkC is linked to a favorable outcome in medulloblastoma.  Proc Natl Acad Sci USA. 1994;  91 12867-12871
• 17 Tait  D M, Thornton-Jones  H, Bloom  H JG, Lemerle  J, Morris-Jones  P. Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I).  Eur J Cancer. 1990;  26 464-469
• 18 Zeltzer  P M, Boyett  J M, Finlay  J L, Albright  A L, Rorke  L B, Milstein  J M, Allen  J C, Stevens  K R, Stanley  P, Li  H, Wisoff  J H, Geyer  J R, McGuire-Cullen  P, Stehbens  J A, Shurin  S B, Packer  R J. Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study.  J Clin Oncol. 1999;  17 832-845