Journal
GENETICS IN MEDICINE
Volume 20, Issue 10, Pages 1196-1205Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gim.2017.241
Keywords
clinical variant reporting; copy-number alteration; formalin-fixed; paraffin-embedded (FFPE); somatic variants; whole-genome sequencing
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Funding
- National Institute for Health Research
- NHS England
- Wellcome Trust
- Department of Health as part of the Health Innovation Challenge Fund
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) (Molecular Diagnostics Theme / Multimodal Pathology Subtheme)
- Cancer Research UK
- Medical Research Council
- Oxford Biomedical Research Centre
- MRC [MC_PC_14089, G0600237, G0700491] Funding Source: UKRI
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Purpose: Fresh-frozen (FF) tissue is the optimal source of DNA for whole-genome sequencing (WGS) of cancer patients. However, it is not always available, limiting the widespread application of WGS in clinical practice. We explored the viability of using formalin-fixed, paraffin-embedded (FFPE) tissues, available routinely for cancer patients, as a source of DNA for clinical WGS. Methods: We conducted a prospective study using DNAs from matched FF, FFPE, and peripheral blood germ-line specimens collected from 52 cancer patients (156 samples) following routine diagnostic protocols. We compared somatic variants detected in FFPE and matching FF samples. Results: We found the single-nucleotide variant agreement reached 71% across the genome and somatic copy-number alterations (CNAs) detection from FFPE samples was suboptimal (0.44 median correlation with FF) due to nonuniform coverage. CNA detection was improved significantly with lower reverse crosslinking temperature in FFPE DNA extraction (80 degrees C or 65 degrees C depending on the methods). Our final data showed somatic variant detection from FFPE for clinical decision making is possible. We detected 98% of clinically actionable variants (including 30/31 CNAs). Conclusion: We present the first prospective WGS study of cancer patients using FFPE specimens collected in a routine clinical environment proving WGS can be applied in the clinic.
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