1. Ultra-sensitive molecular residual disease detection through whole genome sequencing with single-read error correction.
- Author
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Li, Xinxing, Liu, Tao, Bacchiocchi, Antonella, Li, Mengxing, Cheng, Wen, Wittkop, Tobias, Mendez, Fernando L, Wang, Yingyu, Tang, Paul, Yao, Qianqian, Bosenberg, Marcus W, Sznol, Mario, Yan, Qin, Faham, Malek, Weng, Li, Halaban, Ruth, Jin, Hai, and Hu, Zhiqian
- 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
−7 , 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 10−6 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. Synopsis: A novel approach, named AccuScan, was developed for molecular residual disease (MRD) detection and immunotherapy monitoring. This technology uses whole genome sequencing (WGS) with single-read error correction for circulating tumor DNA (ctDNA) analysis. AccuScan reduced WGS error rate to less than 5 × 10−7 , enabling an ultralow limit of detection for circulating tumor variant allele frequency down to the parts-per-million (PPM) range. When applied to MRD detection, AccuScan achieved 90% landmark sensitivity and 100% specificity in post-surgical colorectal cancer patients. AccuScan showed high sensitivity and specificity for MRD detection in esophageal cancer and for immunotherapy monitoring in melanoma patients. AccuScan established a simple, white blood cell-free workflow for tumor-specific variant identification and tumor-informed MRD detection. A novel approach, named AccuScan, was developed for molecular residual disease (MRD) detection and immunotherapy monitoring. This technology uses whole genome sequencing (WGS) with single-read error correction for circulating tumor DNA (ctDNA) analysis. [ABSTRACT FROM AUTHOR]- Published
- 2024
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