Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma

Zhukova, Nataliya, Ramaswamy, Vijay, Remke, Marc, Pfaff, Elke, Shih, David, Martin, Dianna, Castelo-Branco, Pedro, Baskin, Berivan, Ray, Peter, Bouffet, Eric, von Bueren, André, Jones, David T.W., Northcott, Paul, Kool, Marcel, Sturm, Dominik, Pugh, Trevor, Pomeroy, Scott, Cho, Yoon-Jae, Pietsch, Torsten, Gessi, Marco, Rutkowski, Stefan, Bognar, Laszlo, Klekner, Almos, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Eberhart, Charles, Fevre-Montange, Micheele, Fouladi, Maryam, French, Pim, Kros, Max, Grajkowska, Wieslawa, Gupta, Nalin, Weiss, William, Hauser, Peter, Jabado, Nada, Jouvet, Anne, Jung, Shin, Kumabe, Toshihiro, Lach, Boleslaw, Leonard, Jeffrey, Rubin, Joshua, Liau, Linda, Massimi, Luca, Pollack, Ian, Shin Ra, Young, van Meir, Erwin, Zitterbart, Karel, Schüller, Ulrich, Hill, Rebecca, Lindsey, Janet, Schwalbe, Ed, Bailey, Simon, Ellison, David, Hawkins, Cynthia, Malkin, David, Clifford, Steven, Korshunov, Andrey, Pfister, Stefan, Taylor, Michael and Tabori, Uri (2013) Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. Journal of Clinical Oncology, 31 (23). pp. 2927-2935. ISSN 0732-183X

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Official URL: http://dx.doi.org/10.1200/JCO.2012.48.5052

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.

Item Type: Article
Uncontrolled Keywords: oncology
Subjects: A300 Clinical Medicine
C900 Others in Biological Sciences
Department: Faculties > Health and Life Sciences > School of Life Sciences > Applied Sciences
Depositing User: Ay Okpokam
Date Deposited: 11 Oct 2013 10:50
Last Modified: 18 Mar 2016 11:41
URI: http://nrl.northumbria.ac.uk/id/eprint/13891

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