Integrated digital error suppression for improved detection of circulating tumor DNA

By Aaron M. Newman, A. Lovejoy, D. Klass, D. Kurtz, J. Chabon, F. Scherer, H. Stehr, C. Liu, S. Bratman, C. Say and 10 more. Nature Biotechnology, 2016

974 citations recorded by the source corpus.

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 ∼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 105 cfDNA molecules. We anticipate that iDES will aid the noninvasive genotyping and detection of ctDNA in research and clinical settings.

Subfields: Cancer Research, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/94e7718e4e900df3aa12dc2ec6681a145ae3abc2

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Citations in the corpus

Phylogenetic ctDNA analysis depicts early stage lung cancer evolution (2017, positive): “Based on the relationship between tumor volume and ctDNA plasma VAF observed in this study a tumor volume of 0.034 cm3 would equate to a plasma VAF of 1.4 x 10 -4% (95% CI, 6.4 x 10 -6 to 0.0031%), at the extreme of detection limits of current ctDNA platforms 23 .”
Fragment Length of Circulating Tumor DNA (2016, methodology): “Emerging approaches to improve detection of ctDNA include amplicon-based strategies in colorectal cancer [14] and integrated digital error suppression during deep sequencing in lung cancer [15].”
Direct detection of early-stage cancers using circulating tumor DNA (2017, methodology): “By limiting analysis only to a specific set of hotspot variants as others have reported (21), the fraction of cases detected was reduced to 56% of those identified by TEC-Seq.”
Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations (2018, methodology): “Increasingly sophisticated computational techniques are being developed to statistically integrate information from different types of consensus sequences and proportionally weight the certainty of called variants as a way to maximize data recovery while also retaining accuracy 103,104 .”
Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling (2017, methodology): “05 it was classified as detected, in accordance with our prior publications (9,10).”
Enhanced detection of circulating tumor DNA by fragment size analysis (2018, methodology): “Current strategies to improve ctDNA detection rely on increasing depth of sequencing coupled with various error correction methods (2, 13, 14).”
Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors (2017, background): “20 Subclonal cluster 1 (4) Subclonal cluster 3 (7)”