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 Gessi & 41 others Stefan 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

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

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Medulloblastoma
Mutation
Neoplasms
Survival
Germ-Line Mutation
Treatment Failure
Publications
Multivariate Analysis
Survival Rate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zhukova, N., Ramaswamy, V., Remke, M., Pfaff, E., Shih, D. J. H., Martin, D. C., ... 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

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.; Ra, Young Shin; 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: Journal of Clinical Oncology, Vol. 31, No. 23, 10.08.2013, p. 2927-2935.

Research output: Contribution to journalArticle

Zhukova, N, Ramaswamy, V, Remke, M, Pfaff, E, Shih, DJH, Martin, DC, Castelo-Branco, P, Baskin, B, Ray, PN, Bouffet, E, Von Bueren, AO, Jones, DTW, Northcott, PA, Kool, M, Sturm, D, Pugh, TJ, Pomeroy, SL, Cho, Y-J, Pietsch, T, Gessi, M, Rutkowski, S, Bognar, L, Klekner, A, Cho, BK, Kim, SK, Wang, KC, Eberhart, CG, Fevre-Montange, M, Fouladi, M, French, PJ, Kros, M, Grajkowska, WA, Gupta, N, Weiss, WA, Hauser, P, Jabado, N, Jouvet, A, Jung, S, Kumabe, T, Lach, B, Leonard, JR, Rubin, JB, Liau, LM, Massimi, L, Pollack, IF, Ra, YS, Van Meir, EG, Zitterbart, K, Schüller, U, Hill, RM, Lindsey, JC, Schwalbe, EC, Bailey, S, Ellison, DW, Hawkins, C, Malkin, D, Clifford, SC, Korshunov, A, Pfister, S, Taylor, MD & Tabori, U 2013, 'Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma', Journal of Clinical Oncology, vol. 31, no. 23, pp. 2927-2935. https://doi.org/10.1200/JCO.2012.48.5052
Zhukova N, Ramaswamy V, Remke M, Pfaff E, Shih DJH, Martin DC et al. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. Journal of Clinical Oncology. 2013 Aug 10;31(23):2927-2935. https://doi.org/10.1200/JCO.2012.48.5052
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. ; Ra, Young Shin ; 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. / Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. In: Journal of Clinical Oncology. 2013 ; Vol. 31, No. 23. pp. 2927-2935.
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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.",
author = "Nataliya Zhukova and Vijay Ramaswamy and Marc Remke and Elke Pfaff and Shih, {David J.H.} and Martin, {Dianna C.} and Pedro Castelo-Branco and Berivan Baskin and Ray, {Peter N.} and Eric Bouffet and {Von Bueren}, {Andr{\'e} O.} and Jones, {David T.W.} and Northcott, {Paul A.} and Marcel Kool and Dominik Sturm and Pugh, {Trevor J.} and Pomeroy, {Scott L.} and Yoon-Jae Cho and Torsten Pietsch and Marco Gessi and Stefan Rutkowski and Laszlo Bognar and Almos Klekner and Cho, {Byung Kyu} and Kim, {Seung Ki} and Wang, {Kyu Chang} and Eberhart, {Charles G.} and Michelle Fevre-Montange and Maryam Fouladi and French, {Pim J.} and Max Kros and Grajkowska, {Wieslawa A.} and Nalin Gupta and Weiss, {William A.} and Peter Hauser and Nada Jabado and Anne Jouvet and Shin Jung and Toshihiro Kumabe and Boleslaw Lach and Leonard, {Jeffrey R.} and Rubin, {Joshua B.} and Liau, {Linda M.} and Luca Massimi and Pollack, {Ian F.} and Ra, {Young Shin} and {Van Meir}, {Erwin G.} and Karel Zitterbart and Ulrich Sch{\"u}ller and Hill, {Rebecca M.} and Lindsey, {Janet C.} and Schwalbe, {Ed C.} and Simon Bailey and Ellison, {David W.} and Cynthia Hawkins and David Malkin and Clifford, {Steven C.} and Andrey Korshunov and Stefan Pfister and Taylor, {Michael D.} and Uri Tabori",
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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 - Ra, Young Shin

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.

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