Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma
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Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. / Zhukova, Nataliya; Ramaswamy, Vijay; Remke, Marc; Pfaff, Elke; Shih, David J H; Martin, Dianna C; Castelo-Branco, Pedro; Baskin, Berivan; Ray, Peter N; Bouffet, Eric; von Bueren, André O; Jones, David T W; Northcott, Paul A; Kool, Marcel; Sturm, Dominik; Pugh, Trevor J; Pomeroy, Scott L; Cho, Yoon-Jae; Pietsch, Torsten; Gessi, Marco; Rutkowski, Stefan; Bognar, Laszlo; Klekner, Almos; Cho, Byung-Kyu; Kim, Seung-Ki; Wang, Kyu-Chang; Eberhart, Charles G; Fevre-Montange, Michelle; Fouladi, Maryam; French, Pim J; Kros, Max; Grajkowska, Wieslawa A; Gupta, Nalin; Weiss, William A; Hauser, Peter; Jabado, Nada; Jouvet, Anne; Jung, Shin; Kumabe, Toshihiro; Lach, Boleslaw; Leonard, Jeffrey R; Rubin, Joshua B; Liau, Linda M; Massimi, Luca; Pollack, Ian F; Shin Ra, Young; Van Meir, Erwin G; Zitterbart, Karel; Schüller, Ulrich; Hill, Rebecca M; Lindsey, Janet C; Schwalbe, Ed C; Bailey, Simon; Ellison, David W; Hawkins, Cynthia; Malkin, David; Clifford, Steven C; Korshunov, Andrey; Pfister, Stefan; Taylor, Michael D; Tabori, Uri.
In: J CLIN ONCOL, Vol. 31, No. 23, 10.08.2013, p. 2927-35.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -