Acta Neuropathologica

, Volume 124, Issue 5, pp 615–625 | Cite as

Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations

  • Xiao-Yang Liu
  • Noha Gerges
  • Andrey Korshunov
  • Nesrin Sabha
  • Dong-Anh Khuong-Quang
  • Adam M. Fontebasso
  • Adam Fleming
  • Djihad Hadjadj
  • Jeremy Schwartzentruber
  • Jacek Majewski
  • Zhifeng Dong
  • Peter Siegel
  • Steffen Albrecht
  • Sidney Croul
  • David TW Jones
  • Marcel Kool
  • Martje Tonjes
  • Guido Reifenberger
  • Damien Faury
  • Gelareh Zadeh
  • Stefan Pfister
  • Nada Jabado
Original Paper

Abstract

Gliomas are the most common primary brain tumors in children and adults. We recently identified frequent alterations in chromatin remodelling pathways including recurrent mutations in H3F3A and mutations in ATRX (α-thalassemia/mental-retardation-syndrome-X-linked) in pediatric and young adult glioblastoma (GBM, WHO grade IV astrocytoma). H3F3A mutations were specific to pediatric high-grade gliomas and identified in only 3.4 % of adult GBM. Using sequencing and/or immunohistochemical analyses, we investigated ATRX alterations (mutation/loss of expression) and their association with TP53 and IDH1 or IDH2 mutations in 140 adult WHO grade II, III and IV gliomas, 17 pediatric WHO grade II and III astrocytomas and 34 pilocytic astrocytomas. In adults, ATRX aberrations were detected in 33 % of grade II and 46 % of grade III gliomas, as well as in 80 % of secondary and 7 % of primary GBMs. They were absent in the 17 grade II and III astrocytomas in children, and the 34 pilocytic astrocytomas. ATRX alterations closely overlapped with mutations in IDH1/2 (p < 0.0001) and TP53 (p < 0.0001) in samples across all WHO grades. They were prevalent in astrocytomas and oligoastrocytomas, but were absent in oligodendrogliomas (p < 0.0001). No significant association of ATRX mutation/loss of expression and alternative lengthening of telomeres was identified in our cohort. In summary, our data show that ATRX alterations are frequent in adult diffuse gliomas and are specific to astrocytic tumors carrying IDH1/2 and TP53 mutations. Combined alteration of these genes may contribute to drive the neoplastic growth in a major subset of diffuse astrocytomas in adults.

Keywords

Gliomas ATRX IDH TP53 Alternative lengthening of telomeres 

Notes

Acknowledgments

This work was supported by the Cole Foundation, and was funded by the Canadian Institute for Health Research (CIHR) (NJ). X.-Y.L. and A.M.F. are recipients of studentship awards from CIHR. N.J. is the recipient of a ChercheurClinicien Award from Fonds de Recherche en Santé du Québec.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

401_2012_1031_MOESM1_ESM.pdf (888 kb)
Supplementary material, approximately 909 KB.
401_2012_1031_MOESM2_ESM.pdf (705 kb)
Supplementary material, approximately 722 KB.

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Xiao-Yang Liu
    • 1
  • Noha Gerges
    • 1
  • Andrey Korshunov
    • 2
  • Nesrin Sabha
    • 3
  • Dong-Anh Khuong-Quang
    • 1
  • Adam M. Fontebasso
    • 4
  • Adam Fleming
    • 5
  • Djihad Hadjadj
    • 1
  • Jeremy Schwartzentruber
    • 6
  • Jacek Majewski
    • 1
    • 6
  • Zhifeng Dong
    • 7
  • Peter Siegel
    • 7
  • Steffen Albrecht
    • 8
  • Sidney Croul
    • 9
  • David TW Jones
    • 10
  • Marcel Kool
    • 10
  • Martje Tonjes
    • 10
  • Guido Reifenberger
    • 11
  • Damien Faury
    • 1
  • Gelareh Zadeh
    • 3
  • Stefan Pfister
    • 10
    • 12
  • Nada Jabado
    • 1
    • 4
    • 5
    • 13
  1. 1.Department of Human GeneticsMcGill UniversityMontrealCanada
  2. 2.Clinical Cooperation Unit NeuropathologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  3. 3.Division of NeurosurgeryToronto Western HospitalTorontoCanada
  4. 4.Division of Experimental MedicineMcGill UniversityMontrealCanada
  5. 5.Division of Hemato-Oncology, Montreal Children’s HospitalMcGill University Health CentreMontrealCanada
  6. 6.McGill University and Genome Quebec Innovation CentreMontrealCanada
  7. 7.Rosalind and Morris Goodman Cancer Research CentreMcGill UniversityMontrealCanada
  8. 8.Department of Pathology, Montreal Children’s HospitalMcGill University Health CentreMontrealCanada
  9. 9.Department of Laboratory Medicine and Pathobiology, Arthur and Sonia Labatt Brain Tumour Research CentreUniversity Health Network Pathology, University of TorontoTorontoCanada
  10. 10.Division of Molecular GeneticsGerman Cancer Research Center (DKFZ)HeidelbergGermany
  11. 11.Department of NeuropathologyHeinrich-Heine-UniversityDüsseldorfGermany
  12. 12.Department of Pediatric Oncology, Hematology and ImmunologyHeidelberg University HospitalHeidelbergGermany
  13. 13.Department of Pediatrics, The Research Institute of the McGill University Health CentreMcGill UniversityMontrealCanada

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