Reply to J.C. Lindsey et al

During the last year, a renaissance has occurred in the role of TP53 in pediatric medulloblastoma.After initial reports in the early 1990s 1 that stated that TP53 mutations are rare in medulloblastomas, this association was not further explored.A clinical observation that there were no long-term survivors among patients with TP53mutated medulloblastomas in the setting of Li-Fraumeni syndrome (LFS) prompted us to report this observation and open collaborations with Pfaff et al to further explore the issue.Since then, two other publications by both Pfaff et al 2 and by Lindsey et al 3 have added new dimensions to the story.Taken together, the studies indicate that TP53 mutations occur in approximately 5% to 10% of medulloblastomas and are not associated with younger age, metastatic status, or a specific subgroup, 4 which suggests that, in most cases, this is a secondary or late event.Furthermore, a striking association between TP53 and CTNNB1 mutations was observed by Pfaff et al and the British group, 3 whereas this was not the case in the Toronto cohort 5 in which CTNNB1 mutations were not seen.Why CTNNB1 mutant medulloblastomas are so rare in Toronto is not currently clear, but that is not associated with a selection bias as our patient population is community-based without any referral bias.With the addition of the British study 3 and the study by Pfaff et al, 2 it is clear that TP53 mutations are not associated with universal fatality when assessed across medulloblastoma as a whole.However, that TP53 mutations carry no prognostic information has not been adequately tested and there remain many important questions that need to be addressed.First, none of the Toronto patients had CTNNB1 mutations.Combining the two patients with TP53-mutated, non-Wnt/Wingless (WNT)activated medulloblastoma from the study by Lindsey et al, 3 the nine patients from the study by Pfaff et al, 2 and eight patients from our study, 5 13 (68%) of 19 died as a result of their disease.This suggests that, in the non-WNT-subgroup medulloblastomas, TP53 mutations may be an adverse prognostic factor.Secondly, the one patient from the series by Lindsey et al 3 who died as a result of disease had LFS.Since 2006, we have treated 30 patients with the St Jude Medulloblastoma protocol 03.6 Of these, only one patient has died, and he had LFS, which further stresses the need to explore the role of LFS in medulloblastoma.Finally, the discrepancy between the North American 5 and the European 2,3 results needs further study.This may relate to different tumor biology (rarity of CTNNB1 mutations in our patients), but it may also relate to differences in therapy.A classic example of the latter is the acute lymphoblastic leukemia subtype with t(1;19) translocation, which constituted a high-risk group in the Pediatric Oncology Group-based antimetabolite protocols in North America 7 but was not associated with such adverse survival in Berlin-Frankfurt-Mu ¨nster-based European protocols.8 We are currently exploring these important issues together with Pfaff et al.

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