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ctDNA monitoring using patient-specific sequencing and integration of variant reads
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(2020) ctDNA monitoring using patient-specific sequencing and integration of variant reads. Science Translational Medicine, 12 (548). eaaz8084. doi:10.1126/scitranslmed.aaz8084 ISSN 1946-6234.
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WRAP-ctDNA-monitoring-patient-specific-sequencing-integration-variant-reads-Marshall-2020.pdf - Accepted Version - Requires a PDF viewer. Download (1360Kb) | Preview |
Official URL: https://doi.org/10.1126/scitranslmed.aaz8084
Abstract
Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Detection of ctDNA can be challenging in patients with low-volume or residual disease, where plasma contains very few tumor-derived DNA fragments. We show that sensitivity for ctDNA detection in plasma can be improved by analyzing hundreds to thousands of mutations that are first identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) pipeline, which combines custom error-suppression methods and signal-enrichment approaches based on biological features of ctDNA. With this approach, the detection limit in each sample can be estimated independently based on the number of informative reads sequenced across multiple patient-specific loci. We applied INVAR to custom hybrid-capture sequencing data from 176 plasma samples from 105 patients with melanoma, lung, renal, glioma, and breast cancer across both early and advanced disease. By integrating signal across a median of >105 informative reads, ctDNA was routinely quantified to 1 mutant molecule per 100,000, and in some cases with high tumor mutation burden and/or plasma input material, to parts per million. This resulted in median area under the curve (AUC) values of 0.98 in advanced cancers and 0.80 in early-stage and challenging settings for ctDNA detection. We generalized this method to whole-exome and whole-genome sequencing, showing that INVAR may be applied without requiring personalized sequencing panels so long as a tumor mutation list is available. As tumor sequencing becomes increasingly performed, such methods for personalized cancer monitoring may enhance the sensitivity of cancer liquid biopsies.
Item Type: | Journal Article | |||||||||||||||||||||
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Subjects: | R Medicine > RC Internal medicine | |||||||||||||||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Clinical Trials Unit Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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SWORD Depositor: | Library Publications Router | |||||||||||||||||||||
Library of Congress Subject Headings (LCSH): | Tumors -- Diagnosis, Cancer -- Diagnosis, Nucleotide sequence | |||||||||||||||||||||
Journal or Publication Title: | Science Translational Medicine | |||||||||||||||||||||
Publisher: | American Association for the Advancement of Science | |||||||||||||||||||||
ISSN: | 1946-6234 | |||||||||||||||||||||
Official Date: | 17 June 2020 | |||||||||||||||||||||
Dates: |
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Volume: | 12 | |||||||||||||||||||||
Number: | 548 | |||||||||||||||||||||
Article Number: | eaaz8084 | |||||||||||||||||||||
DOI: | 10.1126/scitranslmed.aaz8084 | |||||||||||||||||||||
Status: | Peer Reviewed | |||||||||||||||||||||
Publication Status: | Published | |||||||||||||||||||||
Reuse Statement (publisher, data, author rights): | “This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Translational Medicine on 548, 17/06/2020, DOI: 10.1126/scitranslmed.aaz8084 | |||||||||||||||||||||
Access rights to Published version: | Restricted or Subscription Access | |||||||||||||||||||||
Date of first compliant deposit: | 29 June 2020 | |||||||||||||||||||||
Date of first compliant Open Access: | 29 June 2020 | |||||||||||||||||||||
RIOXX Funder/Project Grant: |
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