Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma

TY - JOUR

T1 - Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma

AU - Zhukova, Nataliya

AU - Ramaswamy, Vijay

AU - Remke, Marc

AU - Pfaff, Elke

AU - Shih, David J H

AU - Martin, Dianna C

AU - Castelo-Branco, Pedro

AU - Baskin, Berivan

AU - Ray, Peter N

AU - Bouffet, Eric

AU - von Bueren, André O

AU - Jones, David T W

AU - Northcott, Paul A

AU - Kool, Marcel

AU - Sturm, Dominik

AU - Pugh, Trevor J

AU - Pomeroy, Scott L

AU - Cho, Yoon-Jae

AU - Pietsch, Torsten

AU - Gessi, Marco

AU - Rutkowski, Stefan

AU - Bognar, Laszlo

AU - Klekner, Almos

AU - Cho, Byung-Kyu

AU - Kim, Seung-Ki

AU - Wang, Kyu-Chang

AU - Eberhart, Charles G

AU - Fevre-Montange, Michelle

AU - Fouladi, Maryam

AU - French, Pim J

AU - Kros, Max

AU - Grajkowska, Wieslawa A

AU - Gupta, Nalin

AU - Weiss, William A

AU - Hauser, Peter

AU - Jabado, Nada

AU - Jouvet, Anne

AU - Jung, Shin

AU - Kumabe, Toshihiro

AU - Lach, Boleslaw

AU - Leonard, Jeffrey R

AU - Rubin, Joshua B

AU - Liau, Linda M

AU - Massimi, Luca

AU - Pollack, Ian F

AU - Shin Ra, Young

AU - Van Meir, Erwin G

AU - Zitterbart, Karel

AU - Schüller, Ulrich

AU - Hill, Rebecca M

AU - Lindsey, Janet C

AU - Schwalbe, Ed C

AU - Bailey, Simon

AU - Ellison, David W

AU - Hawkins, Cynthia

AU - Malkin, David

AU - Clifford, Steven C

AU - Korshunov, Andrey

AU - Pfister, Stefan

AU - Taylor, Michael D

AU - Tabori, Uri

PY - 2013/8/10

Y1 - 2013/8/10

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Cerebellar Neoplasms

KW - Child

KW - Child, Preschool

KW - Female

KW - Gene Expression Profiling

KW - Genes, p53

KW - Humans

KW - Infant

KW - Male

KW - Medulloblastoma

KW - Middle Aged

KW - Mutation

KW - Prognosis

KW - Young Adult

U2 - 10.1200/JCO.2012.48.5052

DO - 10.1200/JCO.2012.48.5052

M3 - SCORING: Journal article

C2 - 23835706

VL - 31

SP - 2927

EP - 2935

JO - J CLIN ONCOL

JF - J CLIN ONCOL

SN - 0732-183X

IS - 23

ER -