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

Marie Wong, Chelsea Mayoh, Loretta M S Lau, Dong-Anh Khuong-Quang, Mark Pinese, Amit Kumar, Paulette Barahona, Emilie E Wilkie, Patricia Sullivan, Rachel Bowen-James, Mustafa Syed, Iñigo Martincorena, Federico Abascal, Alexandra Sherstyuk, Noemi A Bolanos, Jonathan Baber, Peter Priestley, M Emmy M Dolman, Emmy D G Fleuren, Marie-Emilie GauthierEmily V A Mould, Velimir Gayevskiy, Andrew J Gifford, Dylan Grebert-Wade, Patrick A Strong, Elodie Manouvrier, Meera Warby, David M Thomas, Judy Kirk, Katherine Tucker, Tracey O'Brien, Frank Alvaro, Geoffry B McCowage, Luciano Dalla-Pozza, Nicholas G Gottardo, Heather Tapp, Paul Wood, Seong-Lin Khaw, Jordan R Hansford, Andrew S Moore, Murray D Norris, Toby N Trahair, Richard B Lock, Vanessa Tyrrell, Michelle Haber, Glenn M Marshall, David S Ziegler, Paul G Ekert, Mark J Cowley

Research output: Contribution to journalArticlepeer-review

227 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1742-1753
Number of pages12
JournalNature Medicine
Volume26
Issue number11
DOIs
Publication statusPublished or Issued - Nov 2020
Externally publishedYes

Keywords

  • Adolescent
  • Child
  • Child, Preschool
  • DNA Methylation/genetics
  • Epigenome/genetics
  • Female
  • Humans
  • Infant
  • Male
  • Mutation/genetics
  • Neoplasm Proteins/genetics
  • Neoplasms/classification
  • Pediatrics
  • Precision Medicine
  • Risk Factors
  • Transcriptome/genetics
  • Whole Exome Sequencing
  • Whole Genome Sequencing

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