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Acta Neuropathologica

, Volume 131, Issue 2, pp 299–307 | Cite as

Gliomatosis cerebri in children shares molecular characteristics with other pediatric gliomas

  • Alberto BroniscerEmail author
  • Omar Chamdine
  • Scott Hwang
  • Tong Lin
  • Stanley Pounds
  • Arzu Onar-Thomas
  • Sheila Shurtleff
  • Sariah Allen
  • Amar Gajjar
  • Paul Northcott
  • Brent A. Orr
Original Paper

Abstract

Gliomatosis cerebri (GC), a rare and deadly CNS neoplasm characterized by involvement of at least three cerebral lobes, predominantly affects adults. While a few small series have reported its occurrence in children, little is known about the molecular characteristics of pediatric GC. We reviewed clinical, radiological, and histological features of pediatric patients with primary GC treated at our institution over 15 years. Targeted sequencing of mutational hotspots in H3F3A, IDH1/2, and BRAF, and genome-wide analysis of DNA methylation and copy number abnormalities was performed in available tumors. Thirty-two patients [23 (72 %) with type 1 and 9 (28 %) with type 2 GC] were identified. Median age at diagnosis was 10.2 years (range 1.5–19.1). A median of 4 cerebral lobes (range 3–8) was affected at diagnosis. In addition, symmetrical bithalamic involvement was observed in 9 (28 %) patients. Twenty-two patients (69 %) had an anaplastic astrocytoma. Despite aggressive therapy, only two patients younger than 3 years at diagnosis are long-term survivors. Clustering analysis of methylation array data from 18 cases classified tumors as IDH (n = 3, 17 %), G34 (n = 4, 22 %), mesenchymal (n = 3, 17 %), and RTK I ‘PDGFRA’ (n = 8, 44 %). No tumors were classified as K27 subgroup. PDGFRA was the most commonly amplified oncogene in 4 of 22 tumors (18 %). H3F3A p.G34 occurred in all cases classified as G34. Two of 3 cases in the IDH subgroup had IDH1 p.R132H. No H3F3A p.K27 M, IDH2 p.R172, or BRAF p.V600E mutations were observed. There was a trend towards improved survival in the IDH subgroup (P = 0.056). Patients with bithalamic involvement had worse outcomes (P = 0.019). Despite some overlap, the molecular features of pediatric GC are distinct from its adult counterpart. Like in adults, the similarity of genetic and epigenetic characteristics with other infiltrative high-grade gliomas suggests that pediatric GC does not represent a distinct molecular entity.

Keywords

Children DNA methylation profiles Gliomatosis cerebri Molecular classification 

Notes

Acknowledgments

This work was supported by the United States National Institutes of Health Cancer Center Support (CORE) Grant P30 CA21765 and by the American Lebanese Syrian Associated Charities (ALSAC). We thank Geoffrey Neale and John Morris for assistance in performing the methylation studies. We thank Racquel Collins for her assistance in performing targeted sequencing.

Supplementary material

401_2015_1532_MOESM1_ESM.pdf (165 kb)
Supplemental Fig 1 Distribution of large areas of chromosomal gains or losses according to the methylation subgroup. Red and blue rectangles represent areas of chromosomal gains and losses, respectively. Abbreviation: MES, mesenchymal (PDF 164 kb)
401_2015_1532_MOESM2_ESM.pdf (902 kb)
Supplemental Fig 2 Overall survival of 30 pediatric patients with gliomatosis cerebri and histologically confirmed pure astrocytomas based on their tumor grade (PDF 901 kb)
401_2015_1532_MOESM3_ESM.pdf (898 kb)
Supplemental Fig 3 Overall survival of 32 pediatric patients with gliomatosis cerebri based on the presence of contrast enhancement (PDF 897 kb)
401_2015_1532_MOESM4_ESM.pdf (899 kb)
Supplemental Fig 4 Overall survival of type 1 vs. type 2 gliomatosis cerebri in 32 patients (PDF 898 kb)
401_2015_1532_MOESM5_ESM.pdf (900 kb)
Supplemental Fig 5 Overall survival of 18 pediatric patients with gliomatosis cerebri based on MGMT promoter methylation (PDF 900 kb)

References

  1. 1.
    Armstrong GT, Phillips PC, Rorke-Adams LB, Judkins AR, Localio AR, Fisher MJ (2006) Gliomatosis cerebri: 20 years of experience at the Children’s Hospital of Philadelphia. Cancer 107:1597–1606. doi: 10.1002/cncr.22210 CrossRefPubMedGoogle Scholar
  2. 2.
    Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, Irizarry RA (2014) Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics 30:1363–1369. doi: 10.1093/bioinformatics/btu049 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bady P, Sciuscio D, Diserens AC et al (2012) MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status. Acta Neuropathol 124:547–560. doi: 10.1007/s00401-012-1016-2 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Broniscer A, Tatevossian RG, Sabin ND, Klimo P Jr, Dalton J, Lee R, Gajjar A, Ellison DW (2014) Clinical, radiological, histological and molecular characteristics of paediatric epithelioid glioblastoma. Neuropathol Appl Neurobiol 40:327–336. doi: 10.1111/nan.12093 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Chappé C, Riffaud L, Tréguier C et al (2013) Primary gliomatosis cerebri involving gray matter in pediatrics: a distinct entity? A multicenter study of 14 cases. Childs Nerv Syst 29:565–571. doi: 10.1007/s00381-012-2016-1 CrossRefPubMedGoogle Scholar
  6. 6.
    Colosimo C, di Lella GM, Tartaglione T, Riccardi R (2002) Neuroimaging of thalamic tumors in children. Childs Nerv Syst 18:426–439. doi: 10.1007/s00381-002-0607-y CrossRefPubMedGoogle Scholar
  7. 7.
    D’Urso OF, D’Urso PI, Marsigliante S, Storelli C, Luzi G, Gianfreda CD, Montinaro A, Distante A, Ciappetta P (2009) Correlative analysis of gene expression profile and prognosis in patients with gliomatosis cerebri. Cancer 115:3749–3757. doi: 10.1002/cncr.24435 CrossRefPubMedGoogle Scholar
  8. 8.
    Fuller GN, Kros JM (2007) Gliomatosis cerebri. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) WHO classification of tumours of the central nervous system, 4th edn. IARC, Lyon, pp 50–52Google Scholar
  9. 9.
    George E, Settler A, Connors S, Greenfield JP (2015) Pediatric gliomatosis cerebri: a review of 15 Years. J Child Neurol. doi: 10.1177/0883073815596612
  10. 10.
    Hartmann C, Meyer J, Balss J et al (2009) Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 118:469–474. doi: 10.1007/s00401-009-0561-9 CrossRefPubMedGoogle Scholar
  11. 11.
    Herrlinger U, Felsberg J, Küker W et al (2002) Gliomatosis cerebri: molecular pathology and clinical course. Ann Neurol 52:390–399. doi: 10.1002/ana.10297 CrossRefPubMedGoogle Scholar
  12. 12.
    Herrlinger U, Jones DT, Glas M et al (2015) Gliomatosis cerebri: no evidence for a separate brain tumor entity. Acta Neuropathol. doi: 10.1007/s00401-015-1495-z (in press)
  13. 13.
    Hovestadt V, Zapatka M. conumee: enhanced copy-number variation analysis using Illumina 450 k methylation arrays. R package version 0.99.4. In: Bioconductor: open source software for bioinformatics. http://www.bioconductor.org/packages/release/bioc/html/conumee.html. Accessed 1 Sept 2015
  14. 14.
    Jackson S, Patay Z, Howarth R, Pai Panandiker AS, Onar-Thomas A, Gajjar A, Broniscer A (2013) Clinico-radiologic characteristics of long-term survivors of diffuse intrinsic pontine glioma. J Neurooncol 114:339–344. doi: 10.1007/s11060-013-1189-0 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Jennings MT, Frenchman M, Shehab T, Johnson MD, Creasy J, LaPorte K, Dettbarn WD (1995) Gliomatosis cerebri presenting as intractable epilepsy during early childhood. J Child Neurol 10:37–45. doi: 10.1177/088307389501000111 CrossRefPubMedGoogle Scholar
  16. 16.
    Korshunov A, Ryzhova M, Hovestadt V et al (2015) Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol 129:669–678. doi: 10.1007/s00401-015-1405-4 CrossRefPubMedGoogle Scholar
  17. 17.
    Kwon MJ, Kim ST, Kwon MJ et al (2012) Mutated IDH1 is a favorable prognostic factor for type 2 gliomatosis cerebri. Brain Pathol 22:307–317. doi: 10.1111/j.1750-3639.2011.00532 CrossRefPubMedGoogle Scholar
  18. 18.
    Lee X, Gao M, Ji Y, Yu Y, Feng Y, Li Y, Zhang Y, Cheng W, Zhao W (2009) Analysis of differential BRAF(V600E) mutational status in high aggressive papillary thyroid microcarcinoma. Ann Surg Oncol 16:240–245. doi: 10.1245/s10434-008-0233-3 CrossRefPubMedGoogle Scholar
  19. 19.
    Min HS, Kim B, Park SH (2008) Array-based comparative genomic hybridization and immunohistochemical studies in gliomatosis cerebri. J Neurooncol 90:259–266. doi: 10.1007/s11060-008-9665-7 CrossRefPubMedGoogle Scholar
  20. 20.
    Monty S, Tamayo P, Mesirov J, Golub T (2003) Consensus clustering: a resampling-based method for class discovery and visualization of gene expression microarray data. Mach Learn 52:91–118CrossRefGoogle Scholar
  21. 21.
    Narasimhaiah D, Miquel C, Verhamme E, Desclée P, Cosnard G, Godfraind C (2012) IDH1 mutation, a genetic alteration associated with adult gliomatosis cerebri. Neuropathology 32:30–37. doi: 10.1111/j.1440-1789.2011.01216.x CrossRefPubMedGoogle Scholar
  22. 22.
    Perkins GH, Schomer DF, Fuller GN, Allen PK, Maor MH (2003) Gliomatosis cerebri: improved outcome with radiotherapy. Int J Radiat Oncol Biol Phys 56:1137–1146. doi: 10.1016/S0360-3016(03)00293-1 CrossRefPubMedGoogle Scholar
  23. 23.
    R Core Team (2015). R: a language and environment for statistical computing. In: R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/. Accessed 1 Sept 2015
  24. 24.
    Schwartzentruber J, Korshunov A, Liu XY et al (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–231. doi: 10.1038/nature10833 CrossRefPubMedGoogle Scholar
  25. 25.
    Seiz M, Tuettenberg J, Meyer J, Essig M, Schmieder K, Mawrin C, von Deimling A, Hartmann C (2010) Detection of IDH1 mutations in gliomatosis cerebri, but only in patients with additional solid component: evidence for molecular subtypes. Acta Neuropathol 120:261–267. doi: 10.1007/s00401-010-0701-2 CrossRefPubMedGoogle Scholar
  26. 26.
    Sturm D, Witt H, Hovestadt V et al (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425–437. doi: 10.1016/j.ccr.2012.08.024 CrossRefPubMedGoogle Scholar
  27. 27.
    Troyanskaya O, Cantor M, Sherlock G, Brown P, Hastie T, Tibshirani R, Botstein D, Altman RB (2001) Missing value estimation methods for DNA microarrays. Bioinformatics 17:520–525. doi: 10.1093/bioinformatics/17.6.520 CrossRefPubMedGoogle Scholar
  28. 28.
    Ware ML, Hirose Y, Scheithauer BW, Yeh RF, Mayo MC, Smith JS, Chang S, Cha S, Tihan T, Feuerstein BG (2007) Genetic aberrations in gliomatosis cerebri. Neurosurgery 60:150–158. doi: 10.1227/01.NEU.0000249203.73849.5D CrossRefPubMedGoogle Scholar
  29. 29.
    Wu G, Broniscer A, McEachron TA, St. Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome Project et al (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44:251–253. doi: 10.1038/ng.1102 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Wu G, Diaz AK, Paugh BS, St. Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome Project et al (2014) The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46:444–450. doi: 10.1038/ng.2938 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Zhang J, Wu G, Miller CP, St. Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome Project et al (2013) Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 45:602–612. doi: 10.1038/ng.2611 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Alberto Broniscer
    • 1
    • 6
    Email author
  • Omar Chamdine
    • 1
  • Scott Hwang
    • 2
  • Tong Lin
    • 3
  • Stanley Pounds
    • 3
  • Arzu Onar-Thomas
    • 3
  • Sheila Shurtleff
    • 4
  • Sariah Allen
    • 4
  • Amar Gajjar
    • 1
    • 6
  • Paul Northcott
    • 5
  • Brent A. Orr
    • 4
  1. 1.Department of OncologySt. Jude Children’s Research HospitalMemphisUSA
  2. 2.Department of Diagnostic ImagingSt. Jude Children’s Research HospitalMemphisUSA
  3. 3.Department of BiostatisticsSt. Jude Children’s Research HospitalMemphisUSA
  4. 4.Department of PathologySt. Jude Children’s Research HospitalMemphisUSA
  5. 5.Department of Developmental NeurobiologySt. Jude Children’s Research HospitalMemphisUSA
  6. 6.Department of PediatricsUniversity of Tennessee Health Science CenterMemphisUSA

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