Journal article

Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer

Marie Wong, Chelsea Mayoh, Loretta MS Lau, Dong-Anh Khuong-Quang, Mark Pinese, Amit Kumar, Paulette Barahona, Emilie E Wilkie, Patricia Sullivan, Rachel Bowen-James, Mustafa Syed, Inigo Martincorena, Federico Abascal, Alexandra Sherstyuk, Noemi A Bolanos, Jonathan Baber, Peter Priestley, M Emmy M Dolman, Emmy DG Fleuren, Marie-Emilie Gauthier Show all

Nature Medicine | NATURE RESEARCH | Published : 2020

Abstract

The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% in WGS only and 25.0% in RNAseq only). Of these patients, 93.7% had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 central nervous system tumors, methylome analysis confirmed diagn..

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Grants

Awarded by National Health and Medical Research Council of Australia


Awarded by My Room


Funding Acknowledgements

We sincerely thank patients and parents for participating in this study. We thank the many clinicians and health professionals for their time acquiring consenting patients and for collection and coordination of samples and associated clinical data at Sydney Children's Hospital, Randwick; The Children's Hospital at Westmead; the John Hunter Hospital; the Queensland Children's Hospital; the Royal Children's Hospital Melbourne; the Monash Children's Hospital; the Adelaide Women's & Children's Hospital; and the Perth Children's Hospital. We thank M. Weber (Prince of Wales Hospital) for assistance with anatomical pathology expert input. The authors thank the Sydney Children's Tumour Bank Network for providing samples and related clinical information for this study. We thank the staff of the Personalised Medicine Theme of the Children's Cancer Institute for their dedicated work on Zero Childhood Cancer. We thank M. Dinger, B. Lundie, J. Stockmeyer, A. Statham, J. Copty and the staff at the Kinghorn Centre for Clinical Genomics for helpful discussions related to, and rapid processing of, WGS; J. Mattick and M. Dziadek from the Garvan Institute for helpful discussions related to WGS and for supporting fundraising initiatives; S. Eggers and the staff at the Murdoch Children's Research Institute/Victorian Comprehensive Genetics Service for rapid processing of RNAseq; and the staff at the Australian Genome Research Facility for rapid processing of methylation data. We thank the team from the National Computational Infrastructure, which is supported by the Australian Government. We thank G. Asimenos, D. Pollard and the team from DNAnexus for support with genomic data processing and helpful discussions regarding pipeline development. We thank the Australian Federal Government Department of Health, the New South Wales State Government and the Australian Cancer Research Foundation for funding to establish infrastructure to support the Zero Childhood Cancer personalized medicine program. We thank the Kids Cancer Alliance, Cancer Therapeutics Cooperative Research Centre, for supporting the development of a personalized medicine program; Tour de Cure for supporting tumor biobank personnel; The Steven Walter Children's Cancer Foundation and The Hyundai Help 4 Kids Foundation for supporting G.M.M. and P.G.E.; and the Lions Kids Cancer Genome Project, a joint initiative of Lions International Foundation, the Australian Lions Children's Cancer Research Foundation (ALCCRF), the Garvan Institute of Medical Research, the Children's Cancer Institute and the Kids Cancer Centre, Sydney Children's Hospital. Lions International and ALCCRF provided funding to perform WGS and for key personnel, with thanks to J. Collins for project governance and advocacy. We thank the Cure Brain Cancer Foundation for supporting RNA sequencing of patients with brain tumors; the Kids Cancer Project for supporting molecular profiling and molecular and clinical trial personnel; and the University of New South Wales, W. Peters and the Australian Genomics Health Alliance for providing personnel funding support. The New South Wales Ministry of Health-funded Luminesce Alliance provided funding support for computational personnel and infrastructure.The Medical Research Future Fund, the Australian Brain Cancer Mission, the Minderoo Foundation's Collaborate Against Cancer Initiative and funds raised through the Zero Childhood Cancer Capacity Campaign, a joint initiative of the Children's Cancer Institute and the Sydney Children's Hospital Foundation, supported the national clinical trial and associated clinical and research personnel. We thank the Kinghorn Foundation for personnel support. We thank the National Health and Medical Research Council of Australia (fellowships APP1059804 and APP1157871 to R.B.L), the Cancer Institute of New South Wales and New South Wales Health (fellowship funding for M.J.C.). We thank the 2018 Priority-Driven Collaborative Cancer Research Scheme, co-funded by Cancer Australia and My Room, for personnel and computational support (grant no. 1165556 awarded to M.J.C.). Zero Childhood Cancer is a joint initiative led by the Children's Cancer Institute and Sydney Children's Hospital, Randwick.