Prognostic relevance of clinical and biological risk factors in childhood medulloblastoma: results of patients treated in the prospective multicenter trial HIT'91.
OBJECTIVE
To identify better risk stratification systems in childhood medulloblastoma based on clinical factors and analysis of routinely processed formalin-fixed tumor material.


METHODS
Formalin-fixed paraffin-embedded tumor samples from well-documented patients treated within the prospective randomized multicenter trial HIT'91 were analyzed for DNA amplification of c-myc and N-myc (n=133) and mRNA expression of c-myc and trkC (n=104; compared with human cerebellum) using validated methods of quantitative PCR and reverse transcription-PCR. Results were related to clinical data and outcome.


RESULTS
TrkC and c-myc mRNA expression were identified as independent prognostic factors by multivariate analysis. Three risk groups were identified. (a) Favorable risk group: all 8 patients (2 metastatic) with high trkC (>1x human cerebellum) and low c-myc mRNA expression (<or=1x human cerebellum) remained relapse-free [7-year event-free survival (EFS), 100%]. (b) Poor risk group: 10 of 15 patients with metastatic disease and high c-myc and low trkC mRNA expression relapsed (7-year EFS, 33%). (c) Intermediate risk group: the 7-year EFS of the remaining 78 patients was 65%. Among 47 M(0) stage patients, all 10 patients with high trkC mRNA expression remained relapse-free compared with 15 events in 37 patients with low trkC mRNA expression levels (7-year EFS, 100% versus 62%; P=0.056).


CONCLUSIONS
Whereas the collection of fresh-frozen tumor samples remains a major challenge in large clinical trials, routinely processed paraffin-embedded tissue samples can be used to quantitate the prognostic biological markers trkC and c-myc. On prospective validation of cutoff levels, this may lead to improved stratification of treatment for children with medulloblastoma.
Rutkowski
Stefan
S
University Children's Hospital of Wuerzburg, Wuerzburg, Germany. Rutkowski_S@klinik.uni-wuerzburg.de
von Bueren
André
A
von Hoff
Katja
K
Hartmann
Wolfgang
W
Shalaby
Tarek
T
Deinlein
Frank
F
Warmuth-Metz
Monika
M
Soerensen
Niels
N
Emser
Angela
A
Bode
Udo
U
Mittler
Uwe
U
Urban
Christian
C
Benesch
Martin
M
Kortmann
Rolf D
RD
Schlegel
Paul G
PG
Kuehl
Joachim
J
Pietsch
Torsten
T
Grotzer
Michael
M
D000293:Adolescent; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D002528:Cerebellar Neoplasms / Q000175:diagnosis* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000175:diagnosis* / Q000473:pathology; D011446:Prospective Studies; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D020812:Receptor, trkC / Q000235:genetics; D012307:Risk Factors
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D020812:Receptor, trkC