Implementation of DNA Methylation Array Profiling in Pediatric Central Nervous System Tumors: The AIM BRAIN Project: An Australian and New Zealand Children's Haematology/Oncology Group Study

Christine L White; Kathryn M Kinross; Molly K Moore; Elnaz Rasouli; Robyn Strong; Janelle M Jones; Jason E Cain; Dominik Sturm; Felix Sahm; David T W Jones; Stefan M Pfister; Thomas Robertson; Colleen D'Arcy; Michael L Rodriguez; Jason M Dyke; Reimar Junckerstorff; Dharmesh D Bhuva; Melissa J Davis; Paul Wood; Tim Hassall; David S Ziegler; Stewart Kellie; Geoffrey McCowage; Frank Alvaro; Maria Kirby; John A Heath; Karen Tsui; Andrew Dodgshun; David D Eisenstat; Dong-Anh Khuong-Quang; Meaghan Wall; Elizabeth M Algar; Nicholas G Gottardo; Jordan R Hansford

doi:10.1016/j.jmoldx.2023.06.013

Implementation of DNA Methylation Array Profiling in Pediatric Central Nervous System Tumors: The AIM BRAIN Project: An Australian and New Zealand Children's Haematology/Oncology Group Study

J Mol Diagn. 2023 Oct;25(10):709-728. doi: 10.1016/j.jmoldx.2023.06.013. Epub 2023 Jul 28.

Authors

Christine L White¹, Kathryn M Kinross², Molly K Moore³, Elnaz Rasouli³, Robyn Strong², Janelle M Jones², Jason E Cain³, Dominik Sturm⁴, Felix Sahm⁵, David T W Jones⁶, Stefan M Pfister⁷, Thomas Robertson⁸, Colleen D'Arcy⁹, Michael L Rodriguez¹⁰, Jason M Dyke¹¹, Reimar Junckerstorff¹¹, Dharmesh D Bhuva¹², Melissa J Davis¹², Paul Wood¹³, Tim Hassall¹⁴, David S Ziegler¹⁵, Stewart Kellie¹⁶, Geoffrey McCowage¹⁶, Frank Alvaro¹⁷, Maria Kirby¹⁸, John A Heath¹⁹, Karen Tsui²⁰, Andrew Dodgshun²¹, David D Eisenstat²², Dong-Anh Khuong-Quang²³, Meaghan Wall²⁴, Elizabeth M Algar²⁵, Nicholas G Gottardo²⁶, Jordan R Hansford²⁷

Affiliations

¹ Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia; Victorian Clinical Genetics Services, Parkville, Victoria, Australia.
² Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia; Australian and New Zealand Children's Haematology/Oncology Group, Clayton, Victoria, Australia.
³ Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
⁴ Hopp Children's Cancer Centre Heidelberg, Heidelberg, Germany; Division of Pediatric Glioma Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany; Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
⁵ Hopp Children's Cancer Centre Heidelberg, Heidelberg, Germany; Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
⁶ Hopp Children's Cancer Centre Heidelberg, Heidelberg, Germany; Division of Pediatric Glioma Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
⁷ Hopp Children's Cancer Centre Heidelberg, Heidelberg, Germany; Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
⁸ Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
⁹ Department of Pathology, Royal Children's Hospital, Parkville, Victoria, Australia.
¹⁰ Sydney Children's Hospital, Randwick, New South Wales, Australia.
¹¹ PathWest Neuropathology, Royal Perth Hospital, Perth, Western Australia, Australia; Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Western Australia, Australia.
¹² Walter and Eliza Hall Institute, Melbourne, Victoria, Australia; South Australia ImmunoGENomics Cancer Institute, University of Adelaide, Adelaide, South Australia, Australia.
¹³ Monash Children's Hospital, Clayton, Victoria, Australia.
¹⁴ Queensland Children's Hospital, South Brisbane, Queensland, Australia.
¹⁵ Kids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales, Australia; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW), Kensington, New South Wales, Australia; School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.
¹⁶ The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁷ John Hunter Children's Hospital, New Lambton Heights, New South Wales, Australia.
¹⁸ Women's and Children's Hospital, North Adelaide, South Australia, Australia.
¹⁹ Royal Hobart Hospital, Hobart, Tasmania, Australia.
²⁰ Starship Children's Hospital, Grafton, Auckland, New Zealand.
²¹ Christchurch Hospital, Christchurch Central City, Christchurch, New Zealand.
²² Children's Cancer Centre, Royal Children's Hospital, Parkville, Victoria, Australia; Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
²³ Children's Cancer Centre, Royal Children's Hospital, Parkville, Victoria, Australia.
²⁴ Victorian Clinical Genetics Services, Parkville, Victoria, Australia.
²⁵ Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia. Electronic address: [email protected].
²⁶ Perth Children's Hospital, Nedlands, Western Australia, Australia; Telethon Kids Institute, Nedlands, Western Australia, Australia.
²⁷ South Australia ImmunoGENomics Cancer Institute, University of Adelaide, Adelaide, South Australia, Australia; Women's and Children's Hospital, North Adelaide, South Australia, Australia; Children's Cancer Centre, Royal Children's Hospital, Parkville, Victoria, Australia; Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia; South Australia Health and Medical Research Institute, Adelaide, South Australia, Australia.

PMID: 37517472
DOI: 10.1016/j.jmoldx.2023.06.013

Abstract

DNA methylation array profiling for classifying pediatric central nervous system (CNS) tumors is a valuable adjunct to histopathology. However, unbiased prospective and interlaboratory validation studies have been lacking. The AIM BRAIN diagnostic trial involving 11 pediatric cancer centers in Australia and New Zealand was designed to test the feasibility of routine clinical testing and ran in parallel with the Molecular Neuropathology 2.0 (MNP2.0) study at Deutsches Krebsforschungszentrum (German Cancer Research Center). CNS tumors from 269 pediatric patients were prospectively tested on Illumina EPIC arrays, including 104 cases co-enrolled on MNP2.0. Using MNP classifier versions 11b4 and 12.5, we report classifications with a probability score ≥0.90 in 176 of 265 (66.4%) and 213 of 269 (79.2%) cases, respectively. Significant diagnostic information was obtained in 130 of 176 (74%) for 11b4, and 12 of 174 (7%) classifications were discordant with histopathology. Cases prospectively co-enrolled on MNP2.0 gave concordant classifications (99%) and score thresholds (93%), demonstrating excellent test reproducibility and sensitivity. Overall, DNA methylation profiling is a robust single workflow technique with an acceptable diagnostic yield that is considerably enhanced by the extensive subgroup and copy number profile information generated by the platform. The platform has excellent test reproducibility and sensitivity and contributes significantly to CNS tumor diagnosis.

Publication types

Clinical Trial
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Australia
Central Nervous System Neoplasms* / diagnosis
Central Nervous System Neoplasms* / genetics
Child
DNA Methylation* / genetics
Humans
New Zealand
Prospective Studies
Reproducibility of Results