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Title: | Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer. | Authors: | Lau L.M.S.;Baber J.;Priestley P.;Dolman M.E.M.;Fleuren E.D.G.;Gauthier M.-E.;Mould E.V.A.;Gayevskiy V.;Gifford A.J.;Grebert-Wade D.;Mayoh C.;Bolanos N.A.;Khuong-Quang D.-A.;Pinese M.;Kumar A.;Barahona P.;Wilkie E.E.;Sullivan P.;Bowen-James R.;Syed M.;Martincorena I.;Abascal F.;Sherstyuk A.;Strong P.A.;Manouvrier E.;Warby M.;Thomas D.M.;Kirk J.;Tucker K.;O'Brien T.;Alvaro F.;McCowage G.B.;Dalla-Pozza L.;Gottardo N.G.;Tapp H.;Wood P. ;Khaw S.-L.;Hansford J.R.;Moore A.S.;Norris M.D.;Trahair T.N.;Lock R.B.;Tyrrell V.;Haber M.;Marshall G.M.;Ziegler D.S.;Ekert P.G.;Cowley M.J.;Wong M. | Institution: | (Wong, Mayoh, Lau, Pinese, Kumar, Barahona, Wilkie, Sullivan, Bowen-James, Syed, Sherstyuk, Bolanos, Dolman, Fleuren, Gauthier, Mould, Gifford, Grebert-Wade, Strong, Manouvrier, Norris, Trahair, Lock, Tyrrell, Haber, Marshall, Ziegler, Ekert, Cowley) Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, Australia (Wong, Mayoh, Lau, Pinese, Wilkie, Bolanos, Fleuren, Gifford, O'Brien, Norris, Trahair, Lock, Haber, Marshall, Ziegler, Ekert, Cowley) School of Women's and Children's Health, UNSW Sydney, Kensington, NSW, Australia (Wong, Pinese, Gayevskiy, Thomas, Cowley) Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia (Lau, Bolanos, O'Brien, Trahair, Marshall, Ziegler) Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia (Khuong-Quang, Khaw, Hansford) Children's Cancer Centre, Royal Children's Hospital, Parkville, VIC, Australia (Khuong-Quang, Khaw, Ekert) Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia (Kumar, Ekert) Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (Martincorena, Abascal) Wellcome Trust Sanger Institute, Hinxton, United Kingdom (Baber, Priestley) Hartwig Medical Foundation, Amsterdam, Netherlands (Baber, Priestley) Hartwig Medical Foundation Australia, Sydney, NSW, Australia (Gifford) Department of Anatomical Pathology, Prince of Wales Hospital, Randwick, NSW, Australia (Warby, McCowage, Dalla-Pozza) Cancer Centre for Children, The Children's Hospital Westmead, Westmead, NSW, Australia (Kirk) Familial Cancer Service, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, NSW, Australia (Kirk) Sydney Medical School, University of Sydney Centre for Cancer Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia (Tucker) Hereditary Cancer Centre, Prince of Wales Hospital, Randwick, NSW, Australia (Tucker) Prince of Wales Hospital Clinical School, University of New South Wales, Randwick, NSW, Australia (Alvaro) John Hunter Children's Hospital, New Lambton Heights, NSW, Australia (Gottardo) Department of Paediatric and Adolescent Oncology/Haematology, Perth Children's Hospital, Nedlands, WA, Australia (Gottardo) Brain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, Australia (Tapp) Women's and Children's Hospital, Adelaide, SA, Australia (Wood) Monash Children's Hospital, Melbourne, VIC, Australia (Moore) Oncology Service, Oncology Service, Queensland Children's Hospital, Brisbane, QLD, Australia (Moore) Child Health Research Centre, The University of Queensland, Brisbane, QLD, Australia (Norris) University of New South Wales Centre for Childhood Cancer Research, UNSW Sydney, Kensington, NSW, Australia | Issue Date: | 28-Mar-2021 | Copyright year: | 2020 | Publisher: | Nature Research | Place of publication: | United States | Publication information: | Nature Medicine. 26 (11) (pp 1742-1753), 2020. Date of Publication: November 2020. | Journal: | Nature Medicine | 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 diagnosis in 71.1% of patients and contributed to a change of diagnosis in two patients (2.6%). To date, 43 patients have received a recommended therapy, 38 of whom could be evaluated, with 31% showing objective evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, leading to clinical benefit in some patients.Copyright © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. | DOI: | http://monash.idm.oclc.org/login?url= http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1038/s41591-020-1072-4 |
PubMed URL: | 33020650 [http://www.ncbi.nlm.nih.gov/pubmed/?term=33020650] | ISSN: | 1078-8956 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/26859 | Type: | Article | Subjects: | SWI/SNF related matrix associated actin dependent regulator of chromatin subfamily B member 1/ec [Endogenous Compound] transcription factor EZH2/ec [Endogenous Compound] transcriptional regulator ATRX/ec [Endogenous Compound] *transcriptome/ec [Endogenous Compound] unclassified drug cdkn2a/b protein/ec [Endogenous Compound] h3f3a protein/ec [Endogenous Compound] kit protein/ec [Endogenous Compound] mycn protein/ec [Endogenous Compound] nf1 protein/ec [Endogenous Compound] nras protein/ec [Endogenous Compound] pdfgra protein/ec [Endogenous Compound] pik3ca protein/ec [Endogenous Compound] pik3r1 protein/ec [Endogenous Compound] PIK3R2 protein/ec [Endogenous Compound] rb1 protein/ec [Endogenous Compound] protein tyrosine phosphatase SHP 2/ec [Endogenous Compound] epidermal growth factor receptor/ec [Endogenous Compound] adult article cancer chemotherapy cancer patient cancer risk cancer susceptibility central nervous system tumor *childhood cancer/dt [Drug Therapy] chromosome 1q chromosome arm classifier cohort analysis controlled study feasibility study follow up gene amplification gene expression germline mutation hematologic malignancy human loss of function mutation major clinical study *methylome molecular fingerprinting neuroblastoma pilot study point mutation priority journal prospective study RNA sequencing sarcoma signal transduction single nucleotide polymorphism solid malignant neoplasm treatment response tumor associated leukocyte *whole genome sequencing young adult antineoplastic agent/cb [Drug Combination] antineoplastic agent/dt [Drug Therapy] ATM protein/ec [Endogenous Compound] BRG1 protein/ec [Endogenous Compound] cyclin dependent kinase 4/ec [Endogenous Compound] cyclin dependent kinase inhibitor/cb [Drug Combination] epidermal growth factor receptor 2/ec [Endogenous Compound] fibroblast growth factor receptor 1/ec [Endogenous Compound] mammalian target of rapamycin/ec [Endogenous Compound] mammalian target of rapamycin complex 1/ec [Endogenous Compound] mammalian target of rapamycin complex 2/ec [Endogenous Compound] mammalian target of rapamycin inhibitor/cb [Drug Combination] mammalian target of rapamycin inhibitor/dt [Drug Therapy] Myc protein/ec [Endogenous Compound] nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor/cb [Drug Combination] nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor/dt [Drug Therapy] phosphatidylinositol 3 kinase/ec [Endogenous Compound] phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase/ec [Endogenous Compound] protein/ec [Endogenous Compound] protein kinase B/ec [Endogenous Compound] protein p53/ec [Endogenous Compound] cyclin dependent kinase inhibitor/dt [Drug Therapy] feasibility study follow up gene amplification gene expression germline mutation hematologic malignancy human loss of function mutation major clinical study *methylome molecular fingerprinting neuroblastoma pilot study point mutation priority journal prospective study RNA sequencing sarcoma signal transduction single nucleotide polymorphism solid malignant neoplasm treatment response cancer patient *whole genome sequencing young adult cancer chemotherapy Article adult tumor associated leukocyte cancer risk cancer susceptibility central nervous system tumor *childhood cancer / *drug therapy chromosome 1q chromosome arm classifier cohort analysis controlled study |
Type of Clinical Study or Trial: | Observational study (cohort, case-control, cross sectional or survey) |
Appears in Collections: | Articles |
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