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Izquierdo E, Yuan L, George S, et al. Development of a targeted sequencing approach to identify prognostic, predictive and diagnostic markers in paediatric solid tumours. Oncotarget. 2017;8(67):112036-112050doi: 10.18632/oncotarget.23000.
Izquierdo, E., Yuan, L., George, S., Hubank, M., Jones, C., Proszek, P., Shipley, J., Gatz, S. A., Stinson, C., Moore, A. S., Clifford, S. C., Hicks, D., Lindsey, J. C., Hill, R. M., Jacques, T. S., Chalker, J., Thway, K., O'Connor, S., Marshall, L., Moreno, L., Pearson, A., Chesler, L., Walker, B. A., & De Castro, D. G. (2017). Development of a targeted sequencing approach to identify prognostic, predictive and diagnostic markers in paediatric solid tumours. Oncotarget, 8(67), 112036-112050. https://doi.org/10.18632/oncotarget.23000
Izquierdo, Elisa, et al. "Development of a targeted sequencing approach to identify prognostic, predictive and diagnostic markers in paediatric solid tumours." Oncotarget vol. 8,67 (2017): 112036-112050. doi: https://doi.org/10.18632/oncotarget.23000
Izquierdo E, Yuan L, George S, Hubank M, Jones C, Proszek P, Shipley J, Gatz SA, Stinson C, Moore AS, Clifford SC, Hicks D, Lindsey JC, Hill RM, Jacques TS, Chalker J, Thway K, O'Connor S, Marshall L, Moreno L, Pearson A, Chesler L, Walker BA, De Castro DG. Development of a targeted sequencing approach to identify prognostic, predictive and diagnostic markers in paediatric solid tumours. Oncotarget. 2017 Dec 06;8(67):112036-112050. doi: 10.18632/oncotarget.23000. eCollection 2017 Dec 19. PMID: 29340109; PMCID: PMC5762377.
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Oncotarget. 2017 Dec 06;8(67):112036-112050. doi: 10.18632/oncotarget.23000. eCollection 2017 Dec 19.

Development of a targeted sequencing approach to identify prognostic, predictive and diagnostic markers in paediatric solid tumours.

Oncotarget

Elisa Izquierdo, Lina Yuan, Sally George, Michael Hubank, Chris Jones, Paula Proszek, Janet Shipley, Susanne A Gatz, Caedyn Stinson, Andrew S Moore, Steven C Clifford, Debbie Hicks, Janet C Lindsey, Rebecca M Hill, Thomas S Jacques, Jane Chalker, Khin Thway, Simon O'Connor, Lynley Marshall, Lucas Moreno, Andrew Pearson, Louis Chesler, Brian A Walker, David Gonzalez De Castro

Affiliations

  1. Molecular Diagnostics Department, The Institute of Cancer Research and Clinical Genomics, The Royal Marsden NHS Foundation, London, United Kingdom.
  2. Glioma Team, Division of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
  3. Paediatric Tumour Biology, Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom.
  4. Paediatric Drug Development Team, Children and Young People's Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom.
  5. Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
  6. The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
  7. Oncology Service, Children's Health Queensland Hospital and Health Service, Brisbane, Australia.
  8. UQ Child Health Research Centre, The University of Queensland, Brisbane, Australia.
  9. Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, United Kingdom.
  10. Department of Histology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
  11. Developmental Biology and Cancer Programme, UCL GOS Institute of Child Health, London, United Kingdom.
  12. Haematology, Cellular and Molecular Diagnostics Service, UCL GOS Institute of Child Health, London, United Kingdom.
  13. Sarcoma Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom.
  14. Haemato-Oncology Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom.
  15. HNJ-CNIO Clinical Research Unit and Hospital Universitario Niño Jesus, Madrid, Spain.
  16. Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
  17. Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.

PMID: 29340109 PMCID: PMC5762377 DOI: 10.18632/oncotarget.23000

Abstract

The implementation of personalised medicine in childhood cancers has been limited by a lack of clinically validated multi-target sequencing approaches specific for paediatric solid tumours. In order to support innovative clinical trials in high-risk patients with unmet need, we have developed a clinically relevant targeted sequencing panel spanning 311 kb and comprising 78 genes involved in childhood cancers. A total of 132 samples were used for the validation of the panel, including Horizon Discovery cell blends (n=4), cell lines (n=15), formalin-fixed paraffin embedded (FFPE, n=83) and fresh frozen tissue (FF, n=30) patient samples. Cell blends containing known single nucleotide variants (SNVs, n=528) and small insertion-deletions (indels n=108) were used to define panel sensitivities of ≥98% for SNVs and ≥83% for indels [95% CI] and panel specificity of ≥98% [95% CI] for SNVs. FFPE samples performed comparably to FF samples (n=15 paired). Of 95 well-characterised genetic abnormalities in 33 clinical specimens and 13 cell lines (including SNVs, indels, amplifications, rearrangements and chromosome losses), 94 (98.9%) were detected by our approach. We have validated a robust and practical methodology to guide clinical management of children with solid tumours based on their molecular profiles. Our work demonstrates the value of targeted gene sequencing in the development of precision medicine strategies in paediatric oncology.

Keywords: childhood cancer; molecular diagnostics; panel validation; targeted sequencing; targeted therapies

Conflict of interest statement

CONFLICTS OF INTEREST The authors declared no conflicts of interest with the submitted paper.

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