A tailored molecular profiling programme for children with cancer to identify clinically actionable genetic alterations

Sally L George, Elisa Izquierdo, James Campbell, Eleni Koutroumanidou, Paula Proszek, Sabri Jamal, Deborah Hughes, Lina Yuan, Lynley V Marshall, Fernando Carceller, Julia C Chisholm, Sucheta Vaidya, Henry Mandeville, Paola Angelini, Ajla Wasti, Tomas Bexelius, Khin Thway, Susanne A Gatz, Matthew Clarke, Bissan Al-LazikaniGiuseppe Barone, John Anderson, Deborah A Tweddle, David Gonzalez, Brian A Walker, Jack Barton, Sarita Depani, Jessica Eze, Saira W Ahmed, Lucas Moreno, Andrew Pearson, Janet Shipley, Chris Jones, Darren Hargrave, Thomas S Jacques, Michael Hubank, Louis Chesler

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Abstract

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.

Original languageEnglish
Pages (from-to)224-235
Number of pages12
JournalEuropean journal of cancer (Oxford, England : 1990)
Volume121
Early online date19 Sep 2019
DOIs
Publication statusPublished - Nov 2019

Bibliographical note

Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.

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    George, S. L., Izquierdo, E., Campbell, J., Koutroumanidou, E., Proszek, P., Jamal, S., Hughes, D., Yuan, L., Marshall, L. V., Carceller, F., Chisholm, J. C., Vaidya, S., Mandeville, H., Angelini, P., Wasti, A., Bexelius, T., Thway, K., Gatz, S. A., Clarke, M., ... Chesler, L. (2019). A tailored molecular profiling programme for children with cancer to identify clinically actionable genetic alterations. European journal of cancer (Oxford, England : 1990), 121, 224-235. https://doi.org/10.1016/j.ejca.2019.07.027