Abstract 94P
Background
Long read sequencing (LRS) technologies offer a number of advantages for the clinical characterisation of cancer genomes over the short read sequencing (SRS) technologies currently employed in clinical practice. Genomics England in conjunction with NHSE have initiated a pilot programme to establish the clinical utility of Oxford Nanopore® (ONT) LRS for a subset of cancer patients.
Methods
We have developed an approach to generate high depth, paired (50X tumour, 25X normal) whole genome sequences with LRS and a bioinformatics pipeline to call somatic variants. Our pipeline calls Single Nucleotide Variants (SNVs) and small insertions and deletions (indels) with ClairS, Structural Variants (SVs) with Severus and Copy Number Variants (CNVs) with Purple. We have generated sequencing data for over 100 patients through the NHS Genomic Lab Hubs, and approximately 400 patients as part of our research cohorts, focussing on leukaemia, sarcoma and brain tumour patients.
Results
Our ONT cancer analysis pipeline can detect clinically relevant SNVs, CNVs and SVs with precision and recall exceeding 90%. LRS offers a superior view of complex structural variation, for example phasing of SV breakpoints can distinguish multiple events occurring in cis or trans phase. Furthermore, variants in hard-to-map regions of the genome, such as repetitive sequences, that are inaccessible to SRS technology can be analysed using LRS, allowing detection of additional clinically relevant variants. Characterisation of tumour-specific DNA methylation patterns allows for classification of brain tumour subtypes with machine learning tools, with similar accuracy to data generated from methylation arrays. Our pipeline can also detect and characterise methylation of clinically relevant regions, such as the MGMT and BRCA1 promoter regions.
Conclusions
We have demonstrated that cancer genomes can be comprehensively and accurately characterised with ONT sequencing. This data will be made available as a resource for future research. Comparison with the current standard of care testing will be assessed in the context of the clinical impact for each patient group. This will inform recommendations for the use of ONT for standard of care testing.
Editorial acknowledgement
Clinical trial identification
Legal entity responsible for the study
Genomics England.
Funding
Genomics England.
Disclosure
All authors have declared no conflicts of interest.
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