TP53 mutation is frequently associated with CTNNB1 mutation or MYCN amplification and is compatible with long-term survival in medulloblastoma.
OBJECTIVE
The role of TP53 mutations in the tumorigenesis of sporadic medulloblastoma (MB) and the value of TP53 mutation status as a prognostic marker are not yet definitely elucidated. A recent report identified TP53 mutations in MB as an adverse prognostic marker. Hence, the current study was conducted to validate the prognostic role of TP53 mutation in MB and to understand its contribution to tumorigenesis.


METHODS
A comprehensive genetic analysis of 310 MB samples was performed by screening for TP53 mutations and further relating the TP53 mutation status to p53 immunostaining, cytogenetic aberrations, and clinical variables.


RESULTS
Mutation analysis of TP53 revealed mutations in 21 (6.8%) of 310 samples. Germline TP53 mutations were found in two patients with a history suggestive of a hereditary cancer syndrome. TP53 mutation status was not associated with unfavorable prognosis (P = .63) and was not linked to 17p allelic loss but was over-represented in the prognostically favorable WNT subgroup of MB as defined by CTNNB1 mutation (seven of 35 TP53-mutated tumors v 14 of 271 TP53 wild-type tumors; P = .005) and in tumors carrying high-level MYCN amplification (seven of 21 TP53-mutated tumors v 14 of 282 TP53 wild-type tumors; P = .001).


CONCLUSIONS
The contradictory results in the recent literature concerning the prognostic value of TP53 mutation might be explained by different frequencies of WNT MBs, different frequencies of patients with Li-Fraumeni syndrome, and different cumulative doses of alkylating drugs applied in these studies.
German Cancer Research Center, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany.
Elke
E
Pfaff
Marc
M
Remke
Dominik
D
Sturm
Axel
A
Benner
Hendrik
H
Witt
Till
T
Milde
André O
AO
von Bueren
Andrea
A
Wittmann
Anna
A
Schöttler
Norbert
N
Jorch
Norbert
N
Graf
Andreas E
AE
Kulozik
Olaf
O
Witt
Wolfram
W
Scheurlen
Andreas
A
von Deimling
Stefan
S
Rutkowski
Michael D
MD
Taylor
Uri
U
Tabori
Peter
P
Lichter
Andrey
A
Korshunov
Stefan M
SM
Pfister
D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016159:Tumor Suppressor Protein p53; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics*
D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin