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

Area of Science:

• Genomics
• Molecular Biology
• Cancer Research

Background:

• Whole genome sequencing (WGS) of cell-free DNA (cfDNA) shows promise for minimal residual disease (MRD) detection.
• High error rates in WGS currently limit its clinical utility for sensitive MRD detection.

Purpose of the Study:

• Introduce AccuScan, an efficient cfDNA WGS technology with genome-wide error correction.
• Evaluate AccuScan's performance for MRD detection and cancer monitoring.

Main Methods:

• Developed AccuScan for single read-level error correction in cfDNA WGS.
• Assessed analytical sensitivity and specificity for MRD detection.
• Applied AccuScan to predict relapse in colorectal and esophageal cancers.
• Monitored immunotherapy response in melanoma patients using AccuScan-detected ctDNA.

Main Results:

• AccuScan achieved an ultra-low error rate of 4.2 × 10^-7, two orders of magnitude lower than existing methods.
• Demonstrated analytical sensitivity down to 10^-6 VAF with 99% specificity for MRD.
• Achieved 90% sensitivity for relapse prediction in colorectal cancer and 67% in esophageal cancer.
• AccuScan-detected ctDNA dynamics correlated with clinical outcomes in melanoma patients.

Conclusions:

• AccuScan offers a highly accurate WGS solution for sensitive MRD detection.
• Enables detection of circulating tumor DNA (ctDNA) at parts per million levels.
• AccuScan does not require high sample input or personalized reagents, facilitating broader clinical application.