Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma

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

Research output: Contribution to journalArticlepeer-review

243 Citations (Scopus)

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
Pages (from-to)2927-2935
JournalJournal of Clinical Oncology
Volume31
Issue number23
DOIs
Publication statusPublished - 10 Aug 2013

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