Advertisement

Neurological Sciences

, Volume 39, Issue 7, pp 1191–1201 | Cite as

The clinicopathological and prognostic significance of TP53 alteration in K27M mutated gliomas: an individual-participant data meta-analysis

  • Chengya Dong
  • Zhengrong Yuan
  • Qi Li
  • Yajie Wang
Original Article
  • 106 Downloads

Abstract

This study aimed to investigate the impact of TP53 alteration on survival and clinicopathological features of glioma patients with H3K27M mutations. An individual-participant-data (IPD) meta-analysis was performed to investigate the impact of TP53 alteration on survival and clinicopathological features of patients with H3K27M mutations. Three hundred thirty-one individual records from 12 eligible glioma studies involving the H3K27M mutation were finally included in our meta-analysis, and a pooled hazard ratio (HR) of 1.53 (95%CI, 1.10–2.11; P = 0.01) indicated that TP53 alterations were associated with a shorter overall survival. The pooled odds ratios (ORs) indicated that TP53 alterations were significantly associated with the age at diagnosis ≥ 7 years (OR = 1.97, 95%CI = 1.15–3.38, P = 0.01), the status of histone H3.3 mutations (OR = 9.15, 95%CI = 4.18–20.06, P < 0.00001), and high WHO grade histology (III + IV) (OR = 2.70, 95%CI = 1.33–5.48, P = 0.006). However, no association was found between TP53 alterations and gender or tumor location. This IPD meta-analysis suggests that TP53 alteration is a valuable predictor for the prognosis of patients with H3K27M mutated gliomas. TP53 alteration may be used for identifying a subset of patients who potentially benefit from targeted reactivation of TP53 activity.

Keywords

TP53 Glioma Meta-analysis Survival 

Notes

Funding

This work was supported by grants from the National Natural Science Foundation of China (81572474), Natural Science Foundation of Beijing (7152098), and the Science and Technology Development Fund Project of Traditional Chinese Medicine of Beijing (JJ2015-14).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Schwartzentruber J, Korshunov A, Liu XY, Jones DTW, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Quang DAK, Tönjes M, Hovestadt V, Albrecht S, Kool M, Nantel A, Konermann C, Lindroth A, Jäger N, Rausch T, Ryzhova M, Korbel JO, Hielscher T, Hauser P, Garami M, Klekner A, Bognar L, Ebinger M, Schuhmann MU, Scheurlen W, Pekrun A, Frühwald MC, Roggendorf W, Kramm C, Dürken M, Atkinson J, Lepage P, Montpetit A, Zakrzewska M, Zakrzewski K, Liberski PP, Dong Z, Siegel P, Kulozik AE, Zapatka M, Guha A, Malkin D, Felsberg J, Reifenberger G, von Deimling A, Ichimura K, Collins VP, Witt H, Milde T, Witt O, Zhang C, Castelo-Branco P, Lichter P, Faury D, Tabori U, Plass C, Majewski J, Pfister SM, Jabado N (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–231CrossRefPubMedGoogle Scholar
  2. 2.
    Wu G, Broniscer A, McEachron TA et al (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44:251–253CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Zhang RQ, Shi Z, Chen H et al (2015) Biomarker-based prognostic stratification of young adult glioblastoma. Oncotarget 7:5030–5041PubMedCentralGoogle Scholar
  4. 4.
    Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DTW, Konermann C, Pfaff E, Tönjes M, Sill M, Bender S, Kool M, Zapatka M, Becker N, Zucknick M, Hielscher T, Liu XY, Fontebasso AM, Ryzhova M, Albrecht S, Jacob K, Wolter M, Ebinger M, Schuhmann MU, van Meter T, Frühwald MC, Hauch H, Pekrun A, Radlwimmer B, Niehues T, von Komorowski G, Dürken M, Kulozik AE, Madden J, Donson A, Foreman NK, Drissi R, Fouladi M, Scheurlen W, von Deimling A, Monoranu C, Roggendorf W, Herold-Mende C, Unterberg A, Kramm CM, Felsberg J, Hartmann C, Wiestler B, Wick W, Milde T, Witt O, Lindroth AM, Schwartzentruber J, Faury D, Fleming A, Zakrzewska M, Liberski PP, Zakrzewski K, Hauser P, Garami M, Klekner A, Bognar L, Morrissy S, Cavalli F, Taylor MD, van Sluis P, Koster J, Versteeg R, Volckmann R, Mikkelsen T, Aldape K, Reifenberger G, Collins VP, Majewski J, Korshunov A, Lichter P, Plass C, Jabado N, Pfister SM (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425–437CrossRefPubMedGoogle Scholar
  5. 5.
    Korshunov A, Ryzhova M, Hovestadt V, Bender S, Sturm D, Capper D, Meyer J, Schrimpf D, Kool M, Northcott PA, Zheludkova O, Milde T, Witt O, Kulozik AE, Reifenberger G, Jabado N, Perry A, Lichter P, von Deimling A, Pfister SM, Jones DTW (2015) Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol 129:669–678CrossRefPubMedGoogle Scholar
  6. 6.
    Khuong-Quang DA, Buczkowicz P, Rakopoulos P, Liu XY, Fontebasso AM, Bouffet E, Bartels U, Albrecht S, Schwartzentruber J, Letourneau L, Bourgey M, Bourque G, Montpetit A, Bourret G, Lepage P, Fleming A, Lichter P, Kool M, von Deimling A, Sturm D, Korshunov A, Faury D, Jones DT, Majewski J, Pfister SM, Jabado N, Hawkins C (2012) K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 124:439–447CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Buczkowicz P, Bartels U, Bouffet E, Becher O, Hawkins C (2014) Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications. Acta Neuropathol 128:573–581CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 131:803–820CrossRefPubMedGoogle Scholar
  9. 9.
    Bender S, Tang Y, Lindroth AM, Hovestadt V, Jones DTW, Kool M, Zapatka M, Northcott PA, Sturm D, Wang W, Radlwimmer B, Højfeldt JW, Truffaux N, Castel D, Schubert S, Ryzhova M, Şeker-Cin H, Gronych J, Johann PD, Stark S, Meyer J, Milde T, Schuhmann M, Ebinger M, Monoranu CM, Ponnuswami A, Chen S, Jones C, Witt O, Collins VP, von Deimling A, Jabado N, Puget S, Grill J, Helin K, Korshunov A, Lichter P, Monje M, Plass C, Cho YJ, Pfister SM (2013) Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 24:660–672CrossRefPubMedGoogle Scholar
  10. 10.
    Chan KM, Fang D, Gan H, Hashizume R, Yu C, Schroeder M, Gupta N, Mueller S, James CD, Jenkins R, Sarkaria J, Zhang Z (2013) The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev 27:985–990CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Lewis PW, Muller MM, Koletsky MS, Cordero F, Lin S, Banaszynski LA, Garcia BA, Muir TW, Becher OJ, Allis CD (2013) Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma-K27M. Science 340:857–861CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Venneti S, Garimella MT, Sullivan LM, Martinez D, Huse JT, Heguy A, Santi M, Thompson CB, Judkins AR (2013) Evaluation of histone 3 lysine 27 trimethylation (H3K27me3) and enhancer of zest 2 (EZH2) in pediatric glial and glioneuronal tumors shows decreased H3K27me3 in H3F3A K27M mutant glioblastomas. Brain Pathol 23:558–564CrossRefPubMedGoogle Scholar
  13. 13.
    Gessi M, Gielen GH, Dreschmann V, Waha A, Pietsch T (2015) High frequency of H3F3A K27M mutations characterizes pediatric and adult high-grade gliomas of the spinal cord. Acta Neuropathol 130:435–437CrossRefPubMedGoogle Scholar
  14. 14.
    Castel D, Philippe C, Calmon R, le Dret L, Truffaux N, Boddaert N, Pagès M, Taylor KR, Saulnier P, Lacroix L, Mackay A, Jones C, Sainte-Rose C, Blauwblomme T, Andreiuolo F, Puget S, Grill J, Varlet P, Debily MA (2015) Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol 130:815–827CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Buczkowicz P, Hoeman C, Rakopoulos P, Pajovic S, Letourneau L, Dzamba M, Morrison A, Lewis P, Bouffet E, Bartels U, Zuccaro J, Agnihotri S, Ryall S, Barszczyk M, Chornenkyy Y, Bourgey M, Bourque G, Montpetit A, Cordero F, Castelo-Branco P, Mangerel J, Tabori U, Ho KC, Huang A, Taylor KR, Mackay A, Bendel AE, Nazarian J, Fangusaro JR, Karajannis MA, Zagzag D, Foreman NK, Donson A, Hegert JV, Smith A, Chan J, Lafay-Cousin L, Dunn S, Hukin J, Dunham C, Scheinemann K, Michaud J, Zelcer S, Ramsay D, Cain J, Brennan C, Souweidane MM, Jones C, Allis CD, Brudno M, Becher O, Hawkins C (2014) Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet 46:451–456CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Fontebasso AM, Papillon-Cavanagh S, Schwartzentruber J, Nikbakht H, Gerges N, Fiset PO, Bechet D, Faury D, de Jay N, Ramkissoon LA, Corcoran A, Jones DTW, Sturm D, Johann P, Tomita T, Goldman S, Nagib M, Bendel A, Goumnerova L, Bowers DC, Leonard JR, Rubin JB, Alden T, Browd S, Geyer JR, Leary S, Jallo G, Cohen K, Gupta N, Prados MD, Carret AS, Ellezam B, Crevier L, Klekner A, Bognar L, Hauser P, Garami M, Myseros J, Dong Z, Siegel PM, Malkin H, Ligon AH, Albrecht S, Pfister SM, Ligon KL, Majewski J, Jabado N, Kieran MW (2014) Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet 46:462–466CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Taylor KR, Mackay A, Truffaux N, Butterfield YS, Morozova O, Philippe C, Castel D, Grasso CS, Vinci M, Carvalho D, Carcaboso AM, de Torres C, Cruz O, Mora J, Entz-Werle N, Ingram WJ, Monje M, Hargrave D, Bullock AN, Puget S, Yip S, Jones C, Grill J (2014) Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet 46:457–461CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Wu G, Diaz AK, Paugh BS et al (2014) The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46:444–450CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Freed-Pastor WA, Prives C (2012) Mutant p53: one name, many proteins. Genes Dev 26:1268–1286CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Farnebo M, Bykov VJ, Wiman KG (2010) The p53 tumor suppressor: a master regulator of diverse cellular processes and therapeutic target in cancer. Biochem Biophys Res Commun 396:85–89CrossRefPubMedGoogle Scholar
  21. 21.
    Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, vanTuinen P, Ledbetter DH, Barker DF, Nakamura Y, White R, Vogelstein B (1989) Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244:217–221CrossRefPubMedGoogle Scholar
  22. 22.
    Finlay CA Hinds PW, Levine AJ (1989) The p53 proto-oncogene can act as a suppressor of transformation. Cell 57:1083–1093CrossRefPubMedGoogle Scholar
  23. 23.
    Levine AJ, Finlay CA, Hinds PW (2004) P53 is a tumor suppressor gene. Cell 116:S67–S69CrossRefPubMedGoogle Scholar
  24. 24.
    Leroy B, Fournier JL, Ishioka C, Monti P, Inga A, Fronza G, Soussi T (2013) The TP53 website: an integrative resource centre for the TP53 mutation database and TP53 mutant analysis. Nucleic Acids Res 41:D962–D969CrossRefPubMedGoogle Scholar
  25. 25.
    Muller PA, Vousden KH (2014) Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell 25:304–317CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ohgaki H, Kleihues P (2007) Genetic pathway to primary and secondary glioblastoma. Am J Pathol 170:1445–1453CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Wang X, Chen JX, Liu JP, You C, Liu YH, Mao Q (2014) Gain of function of mutant TP53 in glioblastoma: prognosis and response to temozolomide. Ann Surg Oncol 21:1337–1344CrossRefPubMedGoogle Scholar
  28. 28.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188CrossRefPubMedGoogle Scholar
  30. 30.
    Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101CrossRefPubMedGoogle Scholar
  31. 31.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Aihara K, Mukasa A, Gotoh K et al (2013) H3F3A K27M mutations in thalamic gliomas from young adult patients. Neuro-Oncology 16:140–146CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Hoffman LM, DeWire M, Ryall S et al (2016) Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics. ANC 4:1Google Scholar
  34. 34.
    Feng J, Hao S, Pan C, Wang Y, Wu Z, Zhang J, Yan H, Zhang L, Wan H (2015) The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults. Hum Pathol 46:1626–1632CrossRefPubMedGoogle Scholar
  35. 35.
    Misuraca KL, Barton KL, Chung A et al (2014) Pax3 expression enhances PDGF-B-induced brainstem gliomagenesis and characterizes a subset of brainstem glioma. ANC 2:134Google Scholar
  36. 36.
    Nikbakht H, Panditharatna E, Mikael LG, Li R, Gayden T, Osmond M, Ho CY, Kambhampati M, Hwang EI, Faury D, Siu A, Papillon-Cavanagh S, Bechet D, Ligon KL, Ellezam B, Ingram WJ, Stinson C, Moore AS, Warren KE, Karamchandani J, Packer RJ, Jabado N, Majewski J, Nazarian J (2016) Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma. Nat Commun 7:11185CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zhang L, Chen LH, Wan H, Yang R, Wang Z, Feng J, Yang S, Jones S, Wang S, Zhou W, Zhu H, Killela PJ, Zhang J, Wu Z, Li G, Hao S, Wang Y, Webb JB, Friedman HS, Friedman AH, McLendon RE, He Y, Reitman ZJ, Bigner DD, Yan H (2014) Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas. Nat Genet 46:726–730CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Bogler O, Huang HJ, Kleihues P, Cavenee WK (1995) The p53 gene and its role in human brain tumors. Glia 15:308–327CrossRefPubMedGoogle Scholar
  39. 39.
    Migliavacca M, Ottini L, Bazan V, Agnese V, Corsale S, Macaluso M, Lupi R, Dardanoni G, Valerio MR, Pantuso G, Fede GD, Tomasino RM, Gebbia N, Mariani-Costantini R, Russo A (2004) TP53 in gastric cancer: mutations in the l3 loop and LSH motif DNA-binding domains of TP53 predict poor outcome. J Cell Physiol 200:476–485CrossRefPubMedGoogle Scholar
  40. 40.
    Langerod A, Zhao H, Borgan O et al (2007) TP53 mutation status and gene expression profiles are powerful prognostic markers of breast cancer. Breast Cancer Res 9:R30CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Hof J, Krentz S, van Schewick C, Körner G, Shalapour S, Rhein P, Karawajew L, Ludwig WD, Seeger K, Henze G, von Stackelberg A, Hagemeier C, Eckert C, Kirschner-Schwabe R (2011) Mutations and deletions of the TP53 gene predict nonresponse to treatment and poor outcome in first relapse of childhood acute lymphoblastic leukemia. J Clin Oncol 29:3185–3193CrossRefPubMedGoogle Scholar
  42. 42.
    Funato K, Major T, Lewis PW, Allis CD, Tabar V (2014) Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation. Science 346:1529–1533CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Goldberg AD, Banaszynski LA, Noh K-M, Lewis PW, Elsaesser SJ, Stadler S, Dewell S, Law M, Guo X, Li X, Wen D, Chapgier A, DeKelver RC, Miller JC, Lee YL, Boydston EA, Holmes MC, Gregory PD, Greally JM, Rafii S, Yang C, Scambler PJ, Garrick D, Gibbons RJ, Higgs DR, Cristea IM, Urnov FD, Zheng D, Allis CD (2010) Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140:678–691CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Szenker E, Ray-Gallet D, Almouzni G (2011) The double face of the histone variant H3.3. Cell Res 21:421–434CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Michotte A, Neyns B, Chaskis C, Sadones J, in 't Veld P (2004) Neuropathological and molecular aspects of low-grade and high-grade gliomas. Acta Neurol Belg 104:148–153PubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Core Laboratory for Clinical Medical Research, Beijing Tian Tan HospitalCapital Medical UniversityBeijingChina
  2. 2.College of Biological Sciences and TechnologyBeijing Forestry UniversityBeijingChina
  3. 3.Department of Clinical Laboratory, Beijing Ditan HospitalCapital Medical UniversityBeijingPeople’s Republic of China

Personalised recommendations