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Routine molecular subgrouping of medulloblastoma: Bridging the divide between research and the clinic using low-cost, mass spectrometry-based DNA methylomics

Date

07 Oct 2016

Session

CNS tumours

Presenters

Ed Schwalbe

Citation

Annals of Oncology (2016) 27 (6): 103-113. 10.1093/annonc/mdw367

Authors

E. Schwalbe1, D. Hicks1, G. Rafiee1, M. Bashton1, H. Gohlke2, A. Enshaei1, S. Potluri1, J. Matthiesen1, M. Mather1, P. Taleongpong1, R. Chaston3, S. Crosier1, A. Smith4, D. Williamson4, S. Bailey4, S. Clifford4

Author affiliations

  • 1 Paediatric Neurooncology, Northern Institute for Cancer Research University of Newcastle, NE1 4LP - Newcastle upon Tyne/GB
  • 2 Agena Bioscience, Agena, D-22761 - Hamburg/DE
  • 3 Genetic Diagnostics, NewGene, Newcastle upon Tyne/GB
  • 4 Paediatric Neurooncology, Northern Institute for Cancer Research University of Newcastle, Newcastle upon Tyne/GB
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Resources

Abstract 2882

Background

DNA methylation patterns allow the subclassification of medulloblastoma (MB) into 4 molecular subgroups, which inform treatment and risk-stratification. Whilst microarrays to assign subgroup are suitable for research, their clinical utility is limited by expense, platform-specificity, sample quality requirements and practicality. Here, we aimed to develop a low-cost, array-independent, robust subgrouping assay suitable for routine quality-controlled subclassification, including scant, poor-quality, aged samples, and apply it to the previously unassignable PNET4 trial.

Methods

Using a cross-validated classification model, a minimal, multiply-redundant, 17-locus signature was derived to assign subgroup from 220 MBs profiled using Illumina 450k DNA-methylation arrays. We next adapted the MALDI-TOF Mass Spectometry (MassARRAY, Agena Bioscience) iPLEX assay to interrogate DNA methylation following bisulfite treatment. After in vitro validation, the assay was applied to 101 DNA extracts from fresh-frozen, FFPE and nuclear (

Results

95/101 validation samples had high-confidence assignments which recapitulated 450k subgroup calls. Subsequently, high-confidence calls were made for 107/153 PNET4 samples. Notably, a worse survival was observed for standard-risk PNET4 Grp4 patients (EFS 80%; p = 0.01).

Conclusions

MBs can be routinely subgrouped using minimal DNA methylation signatures. The assay is suitable for reliable, robust testing of poor-quality, degraded samples using

Clinical trial identification

SIOP-PNET4: NCT01351870

Legal entity responsible for the study

Newcastle University

Funding

Cancer Research UK The Brain Tumour Charity Children's Cancer Run

Disclosure

All authors have declared no conflicts of interest.

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