Journal
NATURE BIOTECHNOLOGY
Volume 34, Issue 5, Pages 547-555Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt.3520
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Funding
- Department of Defense
- National Cancer Institute [1K99CA187192-01A1, R01CA188298]
- US National Institutes of Health Director's New Innovator Award Program [1-DP2-CA186569]
- US Public Health Service/National Institutes of Health [U01 CA194389]
- Ludwig Institute for Cancer Research
- Stanford Cancer Institute-Developmental Cancer Research Award
- CRK Faculty Scholar Fund
- V-Foundation
- Damon Runyon Cancer Research Foundation
- Siebel Stem Cell Institute
- Thomas and Stacey Siebel Foundation
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High-throughput sequencing of circulating tumor DNA (ctDNA) promises to facilitate personalized cancer therapy. However, low quantities of cell-free DNA (cfDNA) in the blood and sequencing artifacts currently limit analytical sensitivity. To overcome these limitations, we introduce an approach for integrated digital error suppression (iDES). Our method combines in silico elimination of highly stereotypical background artifacts with a molecular barcoding strategy for the efficient recovery of cfDNA molecules. Individually, these two methods each improve the sensitivity of cancer personalized profiling by deep sequencing (CAPP-Seq) by about threefold, and synergize when combined to yield similar to 15-fold improvements. As a result, iDES-enhanced CAPP-Seq facilitates noninvasive variant detection across hundreds of kilobases. Applied to non-small cell lung cancer (NSCLC) patients, our method enabled biopsy-free profiling of EGFR kinase domain mutations with 92% sensitivity and >99.99% specificity at the variant level, and with 90% sensitivity and 96% specificity at the patient level. In addition, our approach allowed monitoring of NSCLC ctDNA down to 4 in 10(5) cfDNA molecules. We anticipate that IDES will aid the noninvasive genotyping and detection of ctDNA in research and clinical settings.
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