ctDNA monitoring using patient-specific sequencing and integration of variant reads

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...

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Veröffentlicht in:Science translational medicine Jg. 12; H. 548
Hauptverfasser: Wan, Jonathan C M, Heider, Katrin, Gale, Davina, Murphy, Suzanne, Fisher, Eyal, Mouliere, Florent, Ruiz-Valdepenas, Andrea, Santonja, Angela, Morris, James, Chandrananda, Dineika, Marshall, Andrea, Gill, Andrew B, Chan, Pui Ying, Barker, Emily, Young, Gemma, Cooper, Wendy N, Hudecova, Irena, Marass, Francesco, Mair, Richard, Brindle, Kevin M, Stewart, Grant D, Abraham, Jean E, Caldas, Carlos, Rassl, Doris M, Rintoul, Robert C, Alifrangis, Constantine, Middleton, Mark R, Gallagher, Ferdia A, Parkinson, Christine, Durrani, Amer, McDermott, Ultan, Smith, Christopher G, Massie, Charles, Corrie, Pippa G, Rosenfeld, Nitzan
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 17.06.2020
Schlagworte:
Biomarkers, Tumor
Circulating Tumor DNA - genetics
DNA, Neoplasm - genetics
High-Throughput Nucleotide Sequencing
Humans
Liquid Biopsy
Mutation - genetics
ISSN:1946-6242, 1946-6242
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Zusammenfassung: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 >10 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.
Bibliographie:ObjectType-Article-1
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content type line 23
ISSN:1946-6242
1946-6242
DOI:10.1126/scitranslmed.aaz8084