DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies

Edward C. Schwalbe, Daniel Williamson, Janet C. Lindsey, Dolores Hamilton, Sarra L. Ryan, Hisham Megahed, M. Garami, P. Hauser, Bozena Dembowska-Baginska, Danuta Perek, Paul A. Northcott, Michael D. Taylor, Roger E. Taylor, David W. Ellison, Simon Bailey, Steven C. Clifford

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Molecular subclassification is rapidly informing the clinical management of medulloblastoma. However, the disease remains associated with poor outcomes and therapy-associated late effects, and the majority of patients are not characterized by a validated prognostic biomarker. Here, we investigated the potential of epigenetic DNA methylation for disease subclassification, particularly in formalin-fixed biopsies, and to identify biomarkers for improved therapeutic individualization. Tumor DNA methylation profiles were assessed, alongside molecular and clinical disease features, in 230 patients primarily from the SIOP-UKCCSG PNET3 clinical trial. We demonstrate by cross-validation in frozen training and formalin-fixed test sets that medulloblastoma comprises four robust DNA methylation subgroups (termed WNT, SHH, G3 and G4), highly related to their transcriptomic counterparts, and which display distinct molecular, clinical and pathological disease characteristics. WNT patients displayed an expected favorable prognosis, while outcomes for SHH, G3 and G4 were equivalent in our cohort. MXI1 and IL8 methylation were identified as novel independent high-risk biomarkers in cross-validated survival models of non-WNT patients, and were validated using non-array methods. Incorporation of MXI1 and IL8 into current survival models significantly improved the assignment of disease risk; 46 % of patients could be classified as 'favorable risk' (>90 % survival) compared to 13 % using current models, while the high-risk group was reduced from 30 to 16 %. DNA methylation profiling enables the robust subclassification of four disease subgroups in frozen and routinely collected/archival formalin-fixed biopsy material, and the incorporation of DNA methylation biomarkers can significantly improve disease-risk stratification. These findings have important implications for future risk-adapted clinical disease management.

Original languageEnglish
Pages (from-to)359-371
Number of pages13
JournalActa Neuropathologica
Volume125
Issue number3
DOIs
Publication statusPublished - Mar 2013

Fingerprint

Medulloblastoma
DNA Fingerprinting
DNA Methylation
Formaldehyde
Biopsy
Biomarkers
Interleukin-8
Survival
Pain Measurement
Disease Management
Epigenomics
Methylation
Clinical Trials
Therapeutics

Keywords

  • Biomarkers
  • Medulloblastoma
  • Methylation
  • Prognosis
  • Subgroups

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

Schwalbe, E. C., Williamson, D., Lindsey, J. C., Hamilton, D., Ryan, S. L., Megahed, H., ... Clifford, S. C. (2013). DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies. Acta Neuropathologica, 125(3), 359-371. https://doi.org/10.1007/s00401-012-1077-2

DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies. / Schwalbe, Edward C.; Williamson, Daniel; Lindsey, Janet C.; Hamilton, Dolores; Ryan, Sarra L.; Megahed, Hisham; Garami, M.; Hauser, P.; Dembowska-Baginska, Bozena; Perek, Danuta; Northcott, Paul A.; Taylor, Michael D.; Taylor, Roger E.; Ellison, David W.; Bailey, Simon; Clifford, Steven C.

In: Acta Neuropathologica, Vol. 125, No. 3, 03.2013, p. 359-371.

Research output: Contribution to journalArticle

Schwalbe, EC, Williamson, D, Lindsey, JC, Hamilton, D, Ryan, SL, Megahed, H, Garami, M, Hauser, P, Dembowska-Baginska, B, Perek, D, Northcott, PA, Taylor, MD, Taylor, RE, Ellison, DW, Bailey, S & Clifford, SC 2013, 'DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies', Acta Neuropathologica, vol. 125, no. 3, pp. 359-371. https://doi.org/10.1007/s00401-012-1077-2
Schwalbe, Edward C. ; Williamson, Daniel ; Lindsey, Janet C. ; Hamilton, Dolores ; Ryan, Sarra L. ; Megahed, Hisham ; Garami, M. ; Hauser, P. ; Dembowska-Baginska, Bozena ; Perek, Danuta ; Northcott, Paul A. ; Taylor, Michael D. ; Taylor, Roger E. ; Ellison, David W. ; Bailey, Simon ; Clifford, Steven C. / DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies. In: Acta Neuropathologica. 2013 ; Vol. 125, No. 3. pp. 359-371.
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