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2024

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An efficient cfDNA whole genome sequencing technology AccuScan by Hu Zhiqian and other teams of Tongji University, which can perform whole genome error correction at a single read level!

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Although whole genome sequencing (WGS) of cell-free DNA(cfDNA) has broad application prospects in detecting molecular residual disease (MRD), the error rate of WGS limits its practical performance.

On August 20, 2024, Hu Zhiqian of Tongji University, Jin Hai of Naval Military Medical University, Ruth Halaban of Yale University and Li Weng of AccuraGen Company of the United States jointly communicatedInEMBO Molecular MedicinePublished online entitled“Ultra-sensitive molecular residual disease detection through whole genome sequencing with single-read error correction”The research paper,The studyIntroduced an efficient cfDNA whole genome sequencing technology AccuScan, which can perform whole genome error correction at a single read level with an error rate of 4.2 × 10− 7, About two orders of magnitude lower than the read-centric denoising method.

Applying the AccuScan to molecular residual disease detection, the sensitivity of the analysis of circulating variant allele frequencies was as low as 106 at a sample level specificity of 99%. In predicting colorectal cancer recurrence, AccuScan showed a 90% landmark response (within 6 weeks after surgery) and a 100 percent specificity. Using samples taken within one week of esophageal cancer surgery, the same showed a sensitivity of 67 percent and a specificity of 100 percent. Circulating tumor DNA(ctDNA) levels and dynamic profiles were consistent with clinical outcomes when AccuScan to monitor immunotherapy in melanoma patients.Overall, AccuScan provide high-precision whole-genome sequencing solutions for molecular residual disease detection, enabling one-in-a-million-range ctDNA detection without the need for large samples or personalized reagents.

Molecular residual disease (MRD) refers to the small number of cancer cells that remain after treatment. Timely and sensitive measurement of MRD is essential for assessing the risk of recurrence and treatment decisions. Circulating tumor DNA(ctDNA) has become a real-time biomarker for MRD detection and monitoring. Studies have shown that the level of cancer-specific somatic mutations in ctDNA correlates with tumor stage, burden, and treatment response to different tumor types.The detection of ctDNA is more sensitive and specific than other blood-based cancer biomarkers, such as circulating tumor cells and cancer antigens.

The initial tumor detection method primarily tests for cancer signals in plasma samples without the need for collection and tumor sequencing, but is less sensitive. Methylation-based cancer detection method analysis sensitivity is about 50%,98% specificity, circulating tumor allele fraction is 3.1 x 10.4. In addition, analysis of combined methylation and mutation signals revealed a clinical sensitivity of 55.6% for predicting colorectal cancer (CRC) recurrence in plasma collected 4 weeks after surgery. Tumor detection is known to utilize tumor-specific somatic mutations from a patient's tumor for MRD analysis, which is highly specific and sensitive.Factors affecting sensitivity include the accuracy of the detection of mutations in the tumor and plasma samples in the body, and the total number of cell-free DNA(cfDNA) molecules detected, which is the product of the number of mutant cells being tracked and the average molecular depth obtained by sequencing.

Whole genome sequencing (WGS) testing is an innovative approach for cancer screening and MRD detection. Tumor-based whole genome sequencing MRD detection uses genome breadth to supplement sequencing depth, which in turn improves sensitivity and breaks through the limitations of input sample size.However, the standardUMIError correction relies on multiple readings per input molecule and is cost prohibitive for WGS applications. Some scholars have used a read-centric support vector machine model to reduce the error rate of the WGS somatic cell single nucleotide variant (SNV) to 4.96 x 10.− 5.By using the cumulative signal of thousands of somatic mutations observed in the tumor genome, the longitudinal sensitivity of the detection of bladder cancer using cumulative ctDNA is 91% and the specificity is 92%. Other WGS technologies that use double-stranded sequencing also have ultra-low error rates,<10− 7However, the conversion rate of these methods is low, making it difficult to achieve low detection limits. An efficient and cost-effective genome-wide error correction method is needed to enable WGS to perform MRD detection with high sensitivity and specificity.

AccuScan as a novel cfDNA WGS technology can suppress genome-wide errors at the single-read level. It provides a white blood cell-free way to identify tumorsspecific variationand detection of tumor-informed MRD. With ultra-low detection limits, minimal sample requirements, fast turnaround times, and comprehensive molecular information, AccuScan have great potential in a wide range of research and clinical applications.In summary, this study presents AccuScan of a whole genome sequencing method for ctDNA detection that utilizes concatemer sequencing for whole genome single read error suppression, enabling rapid and sensitive MRD detection and monitoring in cancer patient plasma samples.

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