Clinically actionable mutation profiles in patients with cancer identified by whole-genome sequencing

  1. Jenny C. Taylor2,4
  1. 1Oxford Molecular Diagnostics Centre, Department of Oncology, University of Oxford, Oxford OX3 9DU, United Kingdom;
  2. 2Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom;
  3. 3Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DU, United Kingdom;
  4. 4Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom;
  5. 5Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom;
  6. 6Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, United Kingdom;
  7. 7Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, United Kingdom;
  8. 8Breast Unit, Royal Marsden NHS Foundation Trust and Kingston NHS Foundation Trust, London SW3 6JJ, United Kingdom;
  9. 9Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, United Kingdom;
  10. 10Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, United Kingdom;
  11. 11Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom;
  12. 12University College London, Cancer Institute and Royal National Orthopaedic NHS Hospital, London WC1E 6BT, United Kingdom;
  13. 13Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford OX3 9DU, United Kingdom;
  14. 14Department of Ear Nose and Throat–Head and Neck Surgery, Oxford University Hospitals, Oxford OX3 9DU, United Kingdom;
  15. 15Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom;
  16. 16The Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria
  1. Corresponding author: jenny.taylor{at}well.ox.ac.uk

Abstract

Next-generation sequencing (NGS) efforts have established catalogs of mutations relevant to cancer development. However, the clinical utility of this information remains largely unexplored. Here, we present the results of the first eight patients recruited into a clinical whole-genome sequencing (WGS) program in the United Kingdom. We performed PCR-free WGS of fresh frozen tumors and germline DNA at 75× and 30×, respectively, using the HiSeq2500 HTv4. Subtracted tumor VCFs and paired germlines were subjected to comprehensive analysis of coding and noncoding regions, integration of germline with somatically acquired variants, and global mutation signatures and pathway analyses. Results were classified into tiers and presented to a multidisciplinary tumor board. WGS results helped to clarify an uncertain histopathological diagnosis in one case, led to informed or supported prognosis in two cases, leading to de-escalation of therapy in one, and indicated potential treatments in all eight. Overall 26 different tier 1 potentially clinically actionable findings were identified using WGS compared with six SNVs/indels using routine targeted NGS. These initial results demonstrate the potential of WGS to inform future diagnosis, prognosis, and treatment choice in cancer and justify the systematic evaluation of the clinical utility of WGS in larger cohorts of patients with cancer.

Footnotes

  • [Supplemental material is available for this article.]

  • Received August 30, 2017.
  • Accepted February 9, 2018.

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.

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  1. doi: 10.1101/mcs.a002279 Cold Spring Harb Mol Case Stud 4: a002279 © 2018 Schuh et al.; Published by Cold Spring Harbor Laboratory Press

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