Advertisement

Journal of Neuro-Oncology

, Volume 121, Issue 3, pp 489–497 | Cite as

Altered global histone-trimethylation code and H3F3A-ATRX mutation in pediatric GBM

  • Pankaj Pathak
  • Prerana Jha
  • Suvendu Purkait
  • Vikas Sharma
  • Vaishali Suri
  • Mehar C. Sharma
  • Mohammed Faruq
  • Ashish Suri
  • Chitra SarkarEmail author
Laboratory Investigation

Abstract

Mutations in H3.3-ATRX-DAXX chromatin remodeling pathway have been reported in pediatric GBMs. H3.3 (H3F3A) mutations may affect transcriptional regulation by altered global histone-methylation. Therefore, we analyzed yet partly understood global histone code (H3K-4/9/27/36) trimethylation pattern in H3F3A-ATRX mutants and wild-type. H3F3A, HIST1H3B, IDH1, ATRX, DAXX and Tp53 mutations were identified by sequencing/immunohistochemistry in 27 pediatric GBMs. Global histone-methylation H3K-4/9/27/36me3 and Polycomb-protein EZH2 expression were evaluated by immunohistochemistry. H3F3A-ATRX mutation was observed in 66.7 % (18/27) of pediatric GBMs. K27M and G34R-H3F3A mutations were found in 37 % (10/27) and 14.8 % (4/27) patients respectively. G34V-H3F3A, HIST1H3B and IDH1 mutations were absent. Notably, commonest global histone-methylation mark lost was H3K27me3 (17/25, 68 %) followed by H3K4me3 (45.5 %, 10/22) and H3K9me3 (18.2 %, 4/22). Global H3K36me3 showed no loss. Most significant observation was loss of one or more histone-trimethylation mark in 80 % (20/25) pediatric GBMs. Notably, simultaneous loss of H3K27me3 and H3K4me3 were present in 7/22 (31.8 %) of pediatric GBMs. Low expression of EZH2 was found in 12/24 (50 %) of cases. However no significant correlation of loss of histone-marks or EZH2 expression with H3F3A-ATRX mutants (loss of at least one histone-marks in 87.5 % (14/16) cases) versus wild-types (loss of at least one histone-marks in 75 % (6/8) cases) was seen. The present study highlights for the first time combinatorial loss of one or more histone-trimethylation marks associated with majority of pediatric GBMs and the finding suggests significant role of histone-code in the molecular biology that underlies pediatric GBMs. Hence therapies for patients with particular combinations of histone modifications present opportunity to design innovative patient-tailored treatment protocols.

Keywords

H3F3A H3K4me3/H3K27me3 H3K9me3 ATRX EZH2 Pediatric glioblastoma 

Notes

Acknowledgements

The authors are thankful to Indian Council of Medical Research (ICMR), Neuro Sciences Centre and Department of Pathology, All India Institute of Medical Sciences, New Delhi, India for funding. The authors are also thankful to Dr. Supriya mallick, Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, for assistance in patient follow up and Dr. Mitali Mukerji, Genomics and Molecular Medicine, (CSIR-IGIB), New Delhi for providing genomics facility for this work.

Conflict of interest

The authors declare that there is no conflict of interest.

Supplementary material

11060_2014_1675_MOESM1_ESM.docx (11 kb)
Supplementary material 1 (DOCX 10 kb)
11060_2014_1675_MOESM2_ESM.docx (12 kb)
Supplementary material 2 (DOCX 11 kb)
11060_2014_1675_MOESM3_ESM.docx (13 kb)
Supplementary material 3 (DOCX 13 kb)
11060_2014_1675_MOESM4_ESM.docx (12 kb)
Supplementary material 4 (DOCX 11 kb)
11060_2014_1675_MOESM5_ESM.docx (14 kb)
Supplementary material 5 (DOCX 13 kb)
11060_2014_1675_MOESM6_ESM.docx (12 kb)
Supplementary material 6 (DOCX 12 kb)

References

  1. 1.
    Broniscer A, Gajjar A (2004) Supratentorial high-grade astrocytoma and diffuse brainstem glioma: two challenges for the pediatric oncologist. Oncologist 9:197–206PubMedCrossRefGoogle Scholar
  2. 2.
    Tamber MS, Rutka JT (2003) Pediatric supratentorial high-grade gliomas. Neurosurg Focus 14:e1 ReviewGoogle Scholar
  3. 3.
    Suri V, Das P, Pathak P, Jain A, Sharma MC et al (2009) Pediatric glioblastomas: a histopathological and molecular genetic study. Neuro Oncol 11:274–280PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Gilheeney SW, Kieran MW (2012) Differences in molecular genetics between pediatric and adult malignant astrocytomas: age matters. Future Oncol 8:549–558PubMedCrossRefGoogle Scholar
  5. 5.
    Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E et al (2012) Driver mutations in histone H3.3 and chromatin remodeling genes in pediatric glioblastoma. Nature 482:226–231PubMedCrossRefGoogle Scholar
  6. 6.
    Appin CL, Brat DJ (2014) Molecular genetics of gliomas. Cancer J 20(1):66–72PubMedCrossRefGoogle Scholar
  7. 7.
    Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS et al (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and nonbrainstem glioblastomas. Nat Genet 44:251–253PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Saratsis AM, Kambhampati M, Snyder K, Yadavilli S, Devaney JM et al (2014) Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes. Acta Neuropathol 127:881–895PubMedCrossRefGoogle Scholar
  9. 9.
    Lewis PW, Elsaesser SJ, Noh KM, Stadler SC, Allis CD (2010) Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc Natl Acad Sci USA 107:14075–14080PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT et al (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425–437PubMedCrossRefGoogle Scholar
  11. 11.
    Bender S, Tang Y, Lindroth AM, Hovestadt V, Jones DT et al (2013) Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 24:660–672PubMedCrossRefGoogle Scholar
  12. 12.
    Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol 6:838–849PubMedCrossRefGoogle Scholar
  13. 13.
    klose RJ, Zhang Y (2007) Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol 8:307–318PubMedCrossRefGoogle Scholar
  14. 14.
    Margueron R, Reinberg D (2011) The Polycomb complex PRC2 and its mark in life. Nature 469:343–349PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Liu L, Xu Z, Zhong L, Wang H, Jiang S et al (2013) Prognostic value of EZH2 expression and activity in renal cell carcinoma: a prospective study. PLoS ONE 8:e81484PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Holm K, Grabau D, Lövgren K, Aradottir S, Gruvberger-Saal S et al (2012) Global H3K27 trimethylation and EZH2 abundance in breast tumor subtypes. Mol Oncol 6:494–506PubMedCrossRefGoogle Scholar
  17. 17.
    Shen L, Cui J, Liang S, Pang Y, Liu P (2013) Update of research on the role of EZH2 in cancer progression. Onco Targets Ther 6:321–324PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Orzan F, Pellegatta S, Poliani PL, Pisati F, Caldera V et al (2011) Enhancer of Zeste 2 (EZH2) is up-regulated in malignant gliomas and in glioma stem-like cells. Neuropathol Appl Neurobiol 37:381–394PubMedCrossRefGoogle Scholar
  19. 19.
    Venneti S, Garimella MT, Sullivan LM, Martinez D, Huse JT et al (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 23:558–564PubMedCrossRefGoogle Scholar
  20. 20.
    Chan KM, Fang D, Gan H, Hashizume R, Yu C et al (2013) The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev 27:985–990PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Lewis PW, Müller MM, Koletsky MS, Cordero F, Lin S et al (2013) Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340:857–861PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Zhang A, Xu B, Sun Y, Lu X, Gu R et al (2012) Dynamic changes of histone H3 trimethylated at positions K4 and K27 in human oocytes and preimplantation embryos. Fertil Steril 98:1009–1016PubMedCrossRefGoogle Scholar
  23. 23.
    Nakazawa T, Kondo T, Ma D, Niu D, Mochizuki K et al (2012) Global histone modification of histone H3 in colorectal cancer and its precursor lesions. Hum Pathol 43:834–842PubMedCrossRefGoogle Scholar
  24. 24.
    Rogenhofer S, Kahl P, Mertens C, Hauser S, Hartmann W et al (2012) Global histone H3 lysine 27 (H3K27) methylation levels and their prognostic relevance in renal cell carcinoma. BJU Int 109:459–465PubMedCrossRefGoogle Scholar
  25. 25.
    Dubuc AM, Remke M, Korshunov A, Northcott PA, Zhan SH et al (2013) Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma. Acta Neuropathol 125:373–384PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Watanabe T, Morinaga S, Akaike M, Numata M, Tamagawa H et al (2012) The cellular level of histone H3 lysine 4 dimethylation correlates with response to adjuvant gemcitabine in Japanese pancreatic cancer patients treated with surgery. Eur J Surg Oncol 38:1051–1057PubMedCrossRefGoogle Scholar
  27. 27.
    Tamagawa H, Oshima T, Numata M, Yamamoto N, Shiozawa M et al (2013) Global histone modification of H3K27 correlates with the outcomes in patients with metachronous liver metastasis of colorectal cancer. Eur J Surg Oncol 39:655–661PubMedCrossRefGoogle Scholar
  28. 28.
    Chen YW, Kao SY, Wang HJ, Yang MH (2013) Histone modification patterns correlate with patient outcome in oral squamous cell carcinoma. Cancer 119:4259–4267PubMedCrossRefGoogle Scholar
  29. 29.
    Chapman-Rothe N, Curry E, Zeller C, Liber D, Stronach E et al (2013) Chromatin H3K27me3/H3K4me3 histone marks define gene sets in high-grade serous ovarian cancer that distinguish malignant, tumour-sustaining and chemo-resistant ovarian tumour cells. Oncogene 32:4586–4592PubMedCrossRefGoogle Scholar
  30. 30.
    Rogenhofer S, Miersch H, Göke F, Kahl P, Wieland WF et al (2013) Histone methylation defines an epigenetic entity in penile squamous cell carcinoma. J Urol 189:1117–1122PubMedCrossRefGoogle Scholar
  31. 31.
    Jha P, Suri V, Sharma V, Singh G, Sharma MC et al (2011) IDH1 mutations in gliomas: first series from a tertiary care centre in India with comprehensive review of literature. Exp Mol Pathol 91:385–393PubMedCrossRefGoogle Scholar
  32. 32.
    Zhang Y, Reinberg D (2001) Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev 15:2343–2360PubMedCrossRefGoogle Scholar
  33. 33.
    Greer EL, Shi Y (2012) Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet 13:343–357PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Venneti S, Felicella MM, Coyne T, Phillips JJ, Gorovets D et al (2013) Histone 3 lysine 9 trimethylation is differentially associated with isocitrate dehydrogenase mutations in oligodendrogliomas and high-grade astrocytomas. J Neuropathol Exp Neurol 72:298–306PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Fontebasso AM, Schwartzentruberentruber J, Khuong-Quang DA, Liu XY, Sturm D et al (2013) Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas. Acta Neuropathol 125:659–669PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Khuong-Quang DA, Buczkowicz P, Rakopoulos P, Liu XY, Fontebasso AM et al (2012) K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 124:439–447PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Fontebasso AM, Liu XY, Sturm D, Jabado N (2013) Chromatin remodeling defects in pediatric and young adult glioblastoma: a tale of a variant histone 3 tail. Brain Pathol 23:210–216PubMedCrossRefGoogle Scholar
  38. 38.
    Venneti S, Santi M, Felicella MM, Yarilin D, Phillips JJ et al (2014) A sensitive and specific histopathologic prognostic marker for H3F3A K27M mutant pediatric glioblastomas. Acta Neuropathol 128(5):743–753PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    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. doi: 10.1007/s00401-014-1319-6 Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Pankaj Pathak
    • 1
  • Prerana Jha
    • 1
  • Suvendu Purkait
    • 1
  • Vikas Sharma
    • 1
  • Vaishali Suri
    • 1
  • Mehar C. Sharma
    • 1
  • Mohammed Faruq
    • 2
  • Ashish Suri
    • 3
  • Chitra Sarkar
    • 1
    Email author
  1. 1.Department of PathologyAll India Institute of Medical Sciences (AIIMS)New DelhiIndia
  2. 2.Genomics and Molecular MedicineCouncil of Scientific and Industrial Research - Institute of Genomics and Integrative Biology (CSIR-IGIB)New DelhiIndia
  3. 3.Department of NeurosurgeryAll India Institute of Medical SciencesNew DelhiIndia

Personalised recommendations