DNA methylation-based profiling for paediatric CNS tumour diagnosis and treatment: a population-based study

Jessica C. Pickles, Amy R. Fairchild, Thomas J. Stone, Lorelle Brownlee, Ashirwad Merve, Shireena A. Yasin, Aimee Avery, Saira W. Ahmed, Olumide Ogunbiyi, Jamie Gonzalez Zapata, Abigail F. Peary, Marie Edwards, Lisa Wilkhu, Carryl Dryden, Dariusz Ladon, Mark Kristiansen, Catherine Rowe, Kathreena M. Kurian, James A.R. Nicoll, Clare MitchellTabitha Bloom, David A. Hilton, Safa Al-Sarraj, Lawrence Doey, Paul N. Johns, Leslie R. Bridges, Aruna Chakrabarty, Azzam Ismail, Nitika Rathi, Khaja Syed, G. Alistair Lammie, Clara Limback-Stanic, Colin Smith, Antonia Torgersen, Frances Rae, Rebecca M. Hill, Steven C. Clifford, Yura Grabovska, Daniel Williamson, Matthew Clarke, Chris Jones, David Capper, Martin Sill, Andreas von Deimling, Stefan M. Pfister, David T.W. Jones, Darren Hargrave, Jane Chalker, Thomas S. Jacques*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

11 Citations (Scopus)
137 Downloads (Pure)


Background: Marked variation exists in the use of genomic data in tumour diagnosis, and optimal integration with conventional diagnostic technology remains uncertain despite several studies reporting improved diagnostic accuracy, selection for targeted treatments, and stratification for trials. Our aim was to assess the added value of molecular profiling in routine clinical practice and the impact on conventional and experimental treatments.

Methods: This population-based study assessed the diagnostic and clinical use of DNA methylation-based profiling in childhood CNS tumours using two large national cohorts in the UK. In the diagnostic cohort—which included routinely diagnosed CNS tumours between Sept 1, 2016, and Sept 1, 2018—we assessed how the methylation profile altered or refined diagnosis in routine clinical practice and estimated how this would affect standard patient management. For the archival cohort of diagnostically difficult cases, we established how many cases could be solved using modern standard pathology, how many could only be solved using the methylation profile, and how many remained unsolvable. 

Findings: Of 484 patients younger than 20 years with CNS tumours, 306 had DNA methylation arrays requested by the neuropathologist and were included in the diagnostic cohort. Molecular profiling added a unique contribution to clinical diagnosis in 107 (35%; 95% CI 30–40) of 306 cases in routine diagnostic practice—providing additional molecular subtyping data in 99 cases, amended the final diagnosis in five cases, and making potentially significant predictions in three cases. We estimated that it could change conventional management in 11 (4%; 95% CI 2–6) of 306 patients. Among 195 historically difficult-to-diagnose tumours in the archival cohort, 99 (51%) could be diagnosed using standard methods, with the addition of methylation profiling solving a further 34 (17%) cases. The remaining 62 (32%) cases were unresolved despite specialist pathology and methylation profiling. Interpretation: Together, these data provide estimates of the impact that could be expected from routine implementation of genomic profiling into clinical practice, and indicate limitations where additional techniques will be required. We conclude that DNA methylation arrays are a useful diagnostic adjunct for childhood CNS tumours.

Original languageEnglish
Pages (from-to)121-130
Number of pages10
JournalThe Lancet Child and Adolescent Health
Issue number2
Early online date27 Nov 2019
Publication statusPublished - 1 Feb 2020

Bibliographical note

The acceptance date for this record is provisional and based upon the month of publication for the article.


  • paediatric brain tumours
  • methylation array
  • molecular pathology
  • neuropathology
  • methylation classifier
  • real world evidence
  • World Health Organisation

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