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

DNA methylation-based profiling for paediatric CNS tumour diagnosis and treatment: a population-based study
DNA methylation-based profiling for paediatric CNS tumour diagnosis and treatment: a population-based study
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.
2352-4650
121-130
Pickles, Jessica C.
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Pickles, Jessica C.
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von Deimling, Andreas
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Pfister, Stefan M.
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Chalker, Jane
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Jacques, Thomas S.
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Pickles, Jessica C., Fairchild, Amy R., Stone, Thomas J., Brownlee, Lorelle, Merve, Ashirwad, Yasin, Shireena A., Avery, Aimee, Ahmed, Saira W., Ogunbiyi, Olumide, Zapata, Jamie Gonzalez, Peary, Abigail F., Edwards, Marie, Wilkhu, Lisa, Dryden, Carryl, Ladon, Dariusz, Kristiansen, Mark, Rowe, Catherine, Kurian, Kathreena M., Nicoll, James, Mitchell, Clare, Bloom, Tabitha, Hilton, David A., Al-Sarraj, Safa, Doey, Lawrence, Johns, Paul N., Bridges, Leslie R., Chakrabarty, Aruna, Ismail, Azzam, Rathi, Nitika, Syed, Khaja, Lammie, G. Alistair, Limback-Stanic, Clara, Smith, Colin, Torgersen, Antonia, Rae, Frances, Hill, Rebecca M., Clifford, Steven C., Grabovska, Yura, Williamson, Daniel, Clarke, Matthew, Jones, Chris, Capper, David, Sill, Martin, von Deimling, Andreas, Pfister, Stefan M., Jones, David T.W., Hargrave, Darren, Chalker, Jane and Jacques, Thomas S. (2020) DNA methylation-based profiling for paediatric CNS tumour diagnosis and treatment: a population-based study. The Lancet Child & Adolescent Health, 4 (2), 121-130. (doi:10.1016/S2352-4642(19)30342-6).

Record type: Article

Abstract

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.

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Accepted/In Press date: 11 October 2019
e-pub ahead of print date: 27 November 2019
Published date: February 2020

Identifiers

Local EPrints ID: 436114
URI: http://eprints.soton.ac.uk/id/eprint/436114
ISSN: 2352-4650
PURE UUID: dbce4a1d-c5ed-441e-8ae3-8a789562620c
ORCID for James Nicoll: ORCID iD orcid.org/0000-0002-9444-7246

Catalogue record

Date deposited: 28 Nov 2019 17:30
Last modified: 26 Nov 2021 05:35

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Contributors

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

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