Clinical-grade validation of whole genome sequencing reveals robust detection of low-frequency variants and copy number alterations in CLL

Jenny Klintman; Katerina Barmpouti; Samantha J L Knight; Pauline Robbe; Hélène Dreau; Ruth Clifford; Kate Ridout; Adam Burns; Adele Timbs; David Bruce; Pavlos Antoniou; Alona Sosinsky; Jennifer Becq; David Bentley; Peter Hillmen; Jenny C Taylor; Mark Caulfield; Anna H Schuh

doi:10.1111/bjh.15406

Clinical-grade validation of whole genome sequencing reveals robust detection of low-frequency variants and copy number alterations in CLL

Br J Haematol. 2018 Aug;182(3):412-417. doi: 10.1111/bjh.15406. Epub 2018 May 29.

Authors

Jenny Klintman¹, Katerina Barmpouti^{1

2}, Samantha J L Knight^{3

4}, Pauline Robbe^{1

5}, Hélène Dreau^{1

2}, Ruth Clifford^{1

5

6}, Kate Ridout¹, Adam Burns¹, Adele Timbs², David Bruce^{1

2}, Pavlos Antoniou⁷, Alona Sosinsky⁷, Jennifer Becq⁸, David Bentley⁸, Peter Hillmen⁹, Jenny C Taylor^{3

4}, Mark Caulfield⁶, Anna H Schuh^{1

2

4}

Affiliations

¹ Molecular Diagnostic Centre, Department of Oncology, University of Oxford, Oxford, UK.
² Oxford University Hospitals, Oxford, UK.
³ NIHR Biomedical Research Centre, Oxford and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁴ Oxford Biomedical Research Centre, Oxford, UK.
⁵ Nuffield Department of Laboratory Sciences, University of Oxford, Oxford, UK.
⁶ Haematology Department, University Hospital Limerick, Limerick, Ireland.
⁷ Genomics England, London, UK.
⁸ Illumina, Chesterford, UK.
⁹ St James' Institute of Oncology, St James' University Hospital, Leeds, UK.

PMID: 29808933
DOI: 10.1111/bjh.15406

Abstract

The 100 000 Genome Project aims to develop a diagnostics platform by introducing whole genome sequencing (WGS) into clinical practice. Samples from patients with chronic lymphocytic leukaemia were subjected to WGS. WGS detection of single nucleotide variants and insertion/deletions were validated by targeted next generation sequencing showing high concordance (96·3%), also for detection of sub-clonal variants and low-frequency TP53 variants. Copy number alteration detection was verified by fluorescent in situ hybridisation and genome-wide single nucleotide polymorphism array (concordances of 86·7% and 92·9%, respectively), confirming adequate sensitivity by WGS. Our results confirm that WGS can provide comprehensive genomic characterisation for clinical trials, drug discovery and, ultimately, precision medicine.

Keywords: CLL; Genomics England; chronic lymphocytic leukaemia; precision medicine; whole genome sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
DNA Copy Number Variations / genetics
Female
High-Throughput Nucleotide Sequencing
Humans
INDEL Mutation / genetics
Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
Male
Middle Aged
Polymorphism, Single Nucleotide / genetics
Whole Genome Sequencing / standards*

Abstract

Publication types

MeSH terms

Grants and funding