Which clinical and biological tumor markers proved predictive in the prospective multicenter trial HIT'91--implications for investigating childhood medulloblastoma.
BACKGROUND
Most recent studies analyzing candidate biological prognostic factors in childhood medulloblastoma (MB) are limited by small patient numbers due to dependence on fresh-frozen tumor material. By contrast, large archives of formalin-fixed, paraffin-embedded MB samples exist from homogeneously treated patients.


METHODS
We have optimized RNA and DNA isolation from formalin-fixed paraffin-embedded MB samples. We then analyzed archived tumor samples from well-documented patients treated within the prospective randomized multicenter trial HIT'91 for DNA amplification of c-myc and N-myc, and mRNA expression of c-myc and trkC.


RESULTS
TrkC and c-myc mRNA expression were identified as independent prognostic factors by multivariate analysis. Three risk groups were identified: 1) Favorable risk group: All 8 patients (2 metastatic) with elevated trkC and reduced c-myc mRNA expression (compared to levels of human cerebellum) remained relapse-free (7-year EFS 100%). 2) Poor risk group: 10 of 15 patients with metastatic disease and high c-myc and low trkC mRNA expression relapsed (7-year EFS 33%). 3) Intermediate risk group: The 7-year EFS of the remaining 78 patients was 65%.


CONCLUSIONS
While the collection of fresh-frozen tumor samples is remaining a major challenge in large clinical trials, routinely processed paraffin-embedded tissue samples can be used to quantitate biological prognostic factors on the DNA and RNA level. Upon prospective validation of cut-off levels, this may lead to better risk-based stratification systems for children with medulloblastoma.
Department of Oncology, University Children's Hospital of Zuerich, Switzerland.
M A
MA
Grotzer
K
K
von Hoff
A O
AO
von Bueren
T
T
Shalaby
W
W
Hartmann
M
M
Warmuth-Metz
A
A
Emser
R D
RD
Kortmann
J
J
Kuehl
T
T
Pietsch
S
S
Rutkowski
D000293:Adolescent; D014408:Biomarkers, Tumor / Q000235:genetics*; D002528:Cerebellar Neoplasms / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015870:Gene Expression; D016259:Genes, myc; D006801:Humans; D008527:Medulloblastoma / Q000175:diagnosis / Q000235:genetics*; D015337:Multicenter Studies as Topic; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D016612:Paraffin Embedding; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D016032:Randomized Controlled Trials as Topic; D020812:Receptor, trkC / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors
D014408:Biomarkers, Tumor; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D020812:Receptor, trkC