A tailored molecular profiling programme for children with cancer to identify clinically actionable genetic alterations.
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Date
2019-11-01ICR Author
Author
George, SL
Izquierdo, E
Campbell, J
Koutroumanidou, E
Proszek, P
Jamal, S
Hughes, D
Yuan, L
Marshall, LV
Carceller, F
Chisholm, JC
Vaidya, S
Mandeville, H
Angelini, P
Wasti, A
Bexelius, T
Thway, K
Gatz, SA
Clarke, M
Al-Lazikani, B
Barone, G
Anderson, J
Tweddle, DA
Gonzalez, D
Walker, BA
Barton, J
Depani, S
Eze, J
Ahmed, SW
Moreno, L
Pearson, A
Shipley, J
Jones, C
Hargrave, D
Jacques, TS
Hubank, M
Chesler, L
Type
Journal Article
Metadata
Show full item recordAbstract
BACKGROUND: For children with cancer, the clinical integration of precision medicine to enable predictive biomarker-based therapeutic stratification is urgently needed. METHODS: We have developed a hybrid-capture next-generation sequencing (NGS) panel, specifically designed to detect genetic alterations in paediatric solid tumours, which gives reliable results from as little as 50 ng of DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue. In this study, we offered an NGS panel, with clinical reporting via a molecular tumour board for children with solid tumours. Furthermore, for a cohort of 12 patients, we used a circulating tumour DNA (ctDNA)-specific panel to sequence ctDNA from matched plasma samples and compared plasma and tumour findings. RESULTS: A total of 255 samples were submitted from 223 patients for the NGS panel. Using FFPE tissue, 82% of all submitted samples passed quality control for clinical reporting. At least one genetic alteration was detected in 70% of sequenced samples. The overall detection rate of clinically actionable alterations, defined by modified OncoKB criteria, for all sequenced samples was 51%. A total of 8 patients were sequenced at different stages of treatment. In 6 of these, there were differences in the genetic alterations detected between time points. Sequencing of matched ctDNA in a cohort of extracranial paediatric solid tumours also identified a high detection rate of somatic alterations in plasma. CONCLUSION: We demonstrate that tailored clinical molecular profiling of both tumour DNA and plasma-derived ctDNA is feasible for children with solid tumours. Furthermore, we show that a targeted NGS panel-based approach can identify actionable genetic alterations in a high proportion of patients.
Subject
Humans
Neoplasms
Neoplasm Recurrence, Local
DNA, Neoplasm
Biopsy
Matched-Pair Analysis
Feasibility Studies
Pilot Projects
Predictive Value of Tests
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Adolescent
Child
Child, Preschool
Infant
Female
Male
Young Adult
High-Throughput Nucleotide Sequencing
Transcriptome
Biomarkers, Tumor
Precision Medicine
Circulating Tumor DNA
Research team
Computational Biology and Chemogenomics
Glioma Team
Paediatric Solid Tumour Biology and Therapeutics
Sarcoma Clinical Trials in children and young people
Sarcoma Molecular Pathology
Translational Genomics
Paediatric and Adolescent Radiotherapy
Language
eng
Date accepted
2019-07-23
License start date
2019-11
Citation
European journal of cancer (Oxford, England : 1990), 2019, 121 pp. 224 - 235
Publisher
ELSEVIER SCI LTD