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Lancet Child Adolesc Health. 2019 Nov 27. pii: S2352-4642(19)30342-6. doi: 10.1016/S2352-4642(19)30342-6. [Epub ahead of print]

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

Author information

1
Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK; Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
2
Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
3
Specialist Integrated Haematology and Malignancy Diagnostic Service-Acquired Genomics, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
4
UCL Genomics, UCL Great Ormond Street Institute of Child Health, London, UK.
5
Department of Neuropathology, North Bristol NHS Trust, Bristol, UK.
6
Brain Tumour Research Centre, University of Bristol, UK.
7
Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK; BRAIN UK, Clinical and Experimental Sciences, University of Southampton, Southampton, UK.
8
BRAIN UK, Clinical and Experimental Sciences, University of Southampton, Southampton, UK.
9
Cellular and Anatomical Pathology, University Hospitals Plymouth NHS Trust, Plymouth, UK.
10
Department of Clinical Neuropathology, Kings College Hospital NHS Trust, London, UK.
11
Department of Cellular Pathology, St George's University Hospital NHS Foundation Trust, London, UK.
12
St James's University Hospital, The Leeds Teaching Hospitals NHS Trust, Leeds, UK.
13
Department of Neuropathology, The Walton Centre NHS Foundation Trust, Liverpool, UK.
14
University Hospital of Wales, Cardiff, UK.
15
Department of Cellular Pathology, Imperial College Healthcare NHS Trust, London, UK.
16
Western General Hospital, NHS Lothian, Edinburgh, UK.
17
Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
18
Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
19
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neuropathology, Berlin, Germany; German Cancer Consortium Partner Site Berlin, German Cancer Research Center, Heidelberg, Germany.
20
Hopp Children's Cancer Center Heidelberg, Heidelberg, Germany.
21
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.
22
Hopp Children's Cancer Center Heidelberg, Heidelberg, Germany; Department of Pediatric Oncology, Hematology, Immunology, and Pulmonology, University Hospital Heidelberg, Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.
23
Hopp Children's Cancer Center Heidelberg, Heidelberg, Germany; Pediatric Glioma Research Group, German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.
24
Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.
25
Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK; Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. Electronic address: t.jacques@ucl.ac.uk.

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.

FUNDING:

The Brain Tumour Charity, Children with Cancer UK, Great Ormond Street Hospital Children's Charity, Olivia Hodson Cancer Fund, Cancer Research UK, and the National Institute of Health Research.

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