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

IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EMBO Molecular Medicine Pub Date : 2024-09-01 Epub Date: 2024-08-20 DOI:10.1038/s44321-024-00115-0
Xinxing Li, Tao Liu, Antonella Bacchiocchi, Mengxing Li, Wen Cheng, Tobias Wittkop, Fernando L Mendez, Yingyu Wang, Paul Tang, Qianqian Yao, Marcus W Bosenberg, Mario Sznol, Qin Yan, Malek Faham, Li Weng, Ruth Halaban, Hai Jin, Zhiqian Hu
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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.

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通过全基因组测序和单线程纠错技术进行超灵敏残留疾病分子检测。
虽然无细胞 DNA(cfDNA)全基因组测序(WGS)在检测分子残留疾病(MRD)方面前景广阔,但其性能却受到 WGS 错误率的限制。在这里,我们介绍一种高效的 cfDNA WGS 技术 AccuScan,它能在单个读数级实现全基因组纠错,错误率为 4.2 × 10-7,比以读数为中心的去噪方法低两个数量级。AccuScan 在 MRD 中的应用表明,其分析灵敏度低至 10-6 循环变异等位基因频率,样本级特异性高达 99%。AccuScan 在预测结直肠癌复发方面显示出 90% 的标志性灵敏度(术后 6 周内)和 100% 的特异性。使用术后一周内采集的样本,AccuScan 对食管癌也显示出 67% 的灵敏度和 100% 的特异性。当 AccuScan 用于监测黑色素瘤患者的免疫疗法时,循环肿瘤 DNA (ctDNA) 水平和动态轮廓与临床结果一致。总之,AccuScan 为 MRD 检测提供了高精度的 WGS 解决方案,可在百万分之一的范围内检测 ctDNA,无需大量样本输入或个性化试剂。
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来源期刊
EMBO Molecular Medicine
EMBO Molecular Medicine 医学-医学:研究与实验
CiteScore
17.70
自引率
0.90%
发文量
105
审稿时长
4-8 weeks
期刊介绍: EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance. To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields: Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention). Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease. Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)
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