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, Tom S Jacques, Michael Hubank, Louis Chesler

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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
Volume121
Publication statusPublished - 11 Sept 2019

Bibliographical note

Co-author. Contributed to the panel set up and to the data analysis. The gene panel is now used as key element in the ongoing CRUK funded SMPaeds trial assessing tumour and germline DNA of paediatric patients with relapsed cancer.
As per email correspondence 4/11/2020 I have significantly contributed to the following: 1) The conception and design of the study , 6) Helping critique the output for important intellectual content

Keywords

  • Circulating tumour DNA
  • Clinical targeted sequencing
  • Paediatric oncology
  • Personalised medicine

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