Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma

Nataliya Zhukova, Vijay Ramaswamy, Marc Remke, Elke Pfaff, David J.H. Shih, Dianna C. Martin, Pedro Castelo-Branco, Berivan Baskin, Peter N. Ray, Eric Bouffet, André O. Von Bueren, David T.W. Jones, Paul A. Northcott, Marcel Kool, Dominik Sturm, Trevor J. Pugh, Scott L. Pomeroy, Yoon Jae Cho, Torsten Pietsch, Marco GessiStefan Rutkowski, Laszlo Bognar, Almos Klekner, Byung Kyu Cho, Seung Ki Kim, Kyu Chang Wang, Charles G. Eberhart, Michelle Fevre-Montange, Maryam Fouladi, Pim J. French, Max Kros, Wieslawa A. Grajkowska, Nalin Gupta, William A. Weiss, Peter Hauser, Nada Jabado, Anne Jouvet, Shin Jung, Toshihiro Kumabe, Boleslaw Lach, Jeffrey R. Leonard, Joshua B. Rubin, Linda M. Liau, Luca Massimi, Ian F. Pollack, Young Shin Ra, Erwin G. Van Meir, Karel Zitterbart, Ulrich Schüller, Rebecca M. Hill, Janet C. Lindsey, Ed C. Schwalbe, Simon Bailey, David W. Ellison, Cynthia Hawkins, David Malkin, Steven C. Clifford, Andrey Korshunov, Stefan Pfister, Michael D. Taylor, Uri Tabori

Research output: Contribution to journalArticle

219 Scopus citations

Abstract

Purpose: Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles. Patients and Methods: We determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas. Results: TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors. Conclusion: Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.

Original languageEnglish (US)
Pages (from-to)2927-2935
Number of pages9
JournalJournal of Clinical Oncology
Volume31
Issue number23
DOIs
StatePublished - Aug 10 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Zhukova, N., Ramaswamy, V., Remke, M., Pfaff, E., Shih, D. J. H., Martin, D. C., Castelo-Branco, P., Baskin, B., Ray, P. N., Bouffet, E., Von Bueren, A. O., Jones, D. T. W., Northcott, P. A., Kool, M., Sturm, D., Pugh, T. J., Pomeroy, S. L., Cho, Y. J., Pietsch, T., ... Tabori, U. (2013). Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. Journal of Clinical Oncology, 31(23), 2927-2935. https://doi.org/10.1200/JCO.2012.48.5052