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Cold Spring Harb Mol Case Stud. 2018 Apr 2;4(2). pii: a002279. doi: 10.1101/mcs.a002279. Print 2018 Apr.

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

Author information

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

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.

KEYWORDS:

colon cancer; cutaneous leiomyosarcoma; endometrial carcinoma; neoplasm of the breast; pharyngeal neoplasm; prostate cancer

PMID:
29610388
PMCID:
PMC5880257
DOI:
10.1101/mcs.a002279
[Indexed for MEDLINE]
Free PMC Article

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