Ultra-sensitive molecular residual disease detection through whole genome sequencing with single-read error correction

While whole genome sequencing (WGS) of cell-free DNA (cfDNA) holds enormous promise for detection of molecular residual disease (MRD), its performance is limited by WGS error rate. Here we introduce AccuScan, an efficient cfDNA WGS technology that enables genome-wide error correction at single read-level, achieving an error rate of 4.2 × 10<sup>-7</sup>, which is about two orders of magnitude lower than a read-centric de-noising method. The application of AccuScan to MRD demonstrated analytical sensitivity down to 10<sup>-6</sup> circulating variant allele frequency at 99% sample-level specificity. AccuScan showed 90% landmark sensitivity (within 6 weeks after surgery) and 100% specificity for predicting relapse in colorectal cancer. It also showed 67% sensitivity and 100% specificity in esophageal cancer using samples collected within one week after surgery. When AccuScan was applied to monitor immunotherapy in melanoma patients, the circulating tumor DNA (ctDNA) levels and dynamic profiles were consistent with clinical outcomes. Overall, AccuScan provides a highly accurate WGS solution for MRD detection, empowering ctDNA detection at parts per million range without requiring high sample input or personalized reagents.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2024-08-20
DOI
https://doi.org/10.1038/s44321-024-00115-0
Citations
7
Primary Topic
Cancer Genomics and Diagnostics
Type
article
Field-Weighted Citation Impact
2.00

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article

Ultra-sensitive molecular residual disease detection through whole genome sequencing with single-read error correction

Tobias Wittkop, Mario Sznol, Paul C. Tang, Hai Jin et al.
7 citations
EMBO Molecular Medicine
Cancer Genomics and Diagnostics
2.00
article

Ultra-sensitive molecular residual disease detection through whole genome sequencing with single-read error correction

Tobias Wittkop, Mario Sznol, Paul C. Tang, Hai Jin, Li Weng, Ruth Halaban, Zhiqian Hu, Qin Yan, Xinxing Li, Fernando L. Méndez, Marcus Bosenberg, Qianqian Yao, Antonella Bacchiocchi, Tao Liu, Yingyu Wang, Mengxing Li, Wen Cheng, Malek Faham
article en
7 citations

Abstract

While whole genome sequencing (WGS) of cell-free DNA (cfDNA) holds enormous promise for detection of molecular residual disease (MRD), its performance is limited by WGS error rate. Here we introduce AccuScan, an efficient cfDNA WGS technology that enables genome-wide error correction at single read-level, achieving an error rate of 4.2 × 10<sup>-7</sup>, which is about two orders of magnitude lower than a read-centric de-noising method. The application of AccuScan to MRD demonstrated analytical sensitivity down to 10<sup>-6</sup> circulating variant allele frequency at 99% sample-level specificity. AccuScan showed 90% landmark sensitivity (within 6 weeks after surgery) and 100% specificity for predicting relapse in colorectal cancer. It also showed 67% sensitivity and 100% specificity in esophageal cancer using samples collected within one week after surgery. When AccuScan was applied to monitor immunotherapy in melanoma patients, the circulating tumor DNA (ctDNA) levels and dynamic profiles were consistent with clinical outcomes. Overall, AccuScan provides a highly accurate WGS solution for MRD detection, empowering ctDNA detection at parts per million range without requiring high sample input or personalized reagents.

EMBO Molecular MedicineVol. 16(9)
Tongji University (CN), Second Military Medical University (CN), Peking University (CN), Yale Cancer Center (US), Yale University (US), Shanghai Medical Information Center (CN), Shanghai Changzheng Hospital (CN), Accuray (United States) (US), Changhai Hospital (CN), Peking University First Hospital (CN), Tongji Hospital (CN)
Yale University, Natural Science Foundation of Shanghai, Tongji University, Tongji Hospital, National Institutes of Health, National Cancer Institute
Openalex Percentile: Top 13%
Cancer Genomics and Diagnostics
2.00
DOIOpen Access PDFOpenAlex
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