Ultra-Deep Sequencing of Plasma-Circulating DNA for the Detection of Tumor- Derived Mutations in Patients with Nonmetastatic Colorectal Cancer

Nguyen, Huu-Thinh; Luong, Bac An; Tran, Duc Huy; Nguyen, Trong-Hieu; Ngo, Quoc Dat; Le, Linh-Thy; Ho, Quoc; Nguyen, Hue-Hanh Thi; Nguyen, Cao Minh; Tran, Vu Uyen; Pham, Truong Vinh Ngoc; Le, M.; Lê, Ngoc An; Le, Trung Kien; Nguyen, Thanh Luan; Pham, Hong-Anh Thi; Le, Hong Thuy; Duong, H.; Hoang, Anh Vu; Nguyen, Hoang Duy; Dinh, Kiet Truong; Phan, Minh-Duy; Nguyen, Hoai-Nghia; Do, Thanh-Thuy Thi; Giang, Hoa; Tran, Le Son; Tran, Tuan Diep

doi:10.1080/07357907.2021.2017951

Cited by 8 publications

(4 citation statements)

References 44 publications

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“…Multi-cancer early detection (MCED) tests can potentially overcome these challenges by simultaneously detecting multiple cancer types from a single test (5). Liquid biopsy, an emerging non-invasive approach for MCED, can capture a wide range of tumor features, including cell free DNA (cfDNA), circulating tumor DNA (ctDNA), exosomes, proteins, mRNA, and metabolites (6,7). Among them, ctDNA has become a promising biomarker for detecting early-stage cancers because it is a carrier of genetic and epigenetic modifications from cancer-derived DNA (8).…”

Section: Introductionmentioning

confidence: 99%

Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization

Nguyen¹,

Nguyễn²,

Doan³

et al. 2023

Preprint

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The non-invasive approach for early cancer detection promises a screening assay accessible for everyone. However, the delivery of this promise is limited due mostly to the high sequencing cost associated with available assays. Here, we developed a multimodal assay called SPOT-MAS (Screening for the Presence Of Tumor by Methylation And Size) to simultaneously profile methylomics, fragmentomics, copy number, and end motifs in a single workflow using targeted and shallow genome-wide sequencing of cell-free DNA. We applied SPOT-MAS to 738 nonmetastatic patients with breast, colorectal, gastric, lung and liver cancer, and 1,550 healthy controls. SPOT-MAS detected the five cancer types with a sensitivity of 72.4% and specificity of 97.0%, with AUC of 0.95 (95% CI 0.93-0.96). For tumor-of-origin, a graph convolutional neural network was adopted and could achieve an accuracy of 0.7. In conclusion, our study demonstrates comparable performance to other early cancer detection assays while requiring significantly lower sequencing depth, making it economically feasible for population-wide screening.

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Section: Introductionmentioning

confidence: 99%

Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization

Nguyen¹,

Nguyễn²,

Doan³

et al. 2023

Preprint

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“…In MCED, the blood-based liquid biopsy (LB) approaches have the potential to revolutionize cancer screening by enabling early detection of multiple types of cancer through a simple blood draw (4). LB assays detect specific cancer-related biomolecules including circulating tumour cells (CTC), circulating tumor DNA (ctDNA), circulating free RNA (cfRNA) and exosomes (5)(6)(7)(8). Of these, ctDNA released into the circulation when tumor cells undergo apoptotic and necrotic cell death processes has been extensively studied due to its tissue-and cancer-type specificity (5,6,(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

“…LB assays detect specific cancer-related biomolecules including circulating tumour cells (CTC), circulating tumor DNA (ctDNA), circulating free RNA (cfRNA) and exosomes (5)(6)(7)(8). Of these, ctDNA released into the circulation when tumor cells undergo apoptotic and necrotic cell death processes has been extensively studied due to its tissue-and cancer-type specificity (5,6,(9)(10)(11). Recently, the landscape of MCED tests based on detecting methylation changes in cfDNA has evolved.…”

Section: Introductionmentioning

confidence: 99%

Analytical and clinical validation of a circulating tumor DNA-based assay for multi-cancer early detection

Dang Nguyen,

Hanh Nguyen,

et al. 2023

Preprint

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The development of multi-cancer early detection (MCED) through a single blood test has emerged as a promising method for improving the efficiency of early cancer detection and benefiting population health. However, the lack of analytical validation and clinical evidence for their utility in diverse populations have prevented their use in clinical practice. To address these challenges, we conducted a comprehensive analytical and clinical validation for an MCED test, SPOT-MAS (Screening for the Presence Of Tumor by DNA Methylation And Size). The analytical validation was to establish the limit of detection, reproducibility of test results and assess the impact of potential interferents on test performance. Specifically, SPOT-MAS could detect at least 50% of cancer samples at a specificity of 98% if the samples have tumor fraction more than 0.049 (95% CI: 0.043-0.059). The results were consistently reproduced for both intra- and inter-batch analysis. Moreover, our test remained robust at hemoglobin contamination of 500 mg/dl and genomic DNA contamination of up to 100%. To validate the performance of SPOT-MAS test in clinical settings, we launched a multi-center prospective trial, named K-DETEK, of 10,027 asymptomatic participants in Vietnam. Our assay achieved a positive predictive value of 58.14% (95%CI: 43.33-71.62) with 84.00% (95%CI: 65.35-93.60) accuracy in predicting tumor location and a negative predictive value of 99.92% (95%CI: 99.83-99.96). To our knowledge, this is the first and largest prospective validation study in Asia supporting the utility of SPOT-MAS as a multi-cancer blood test for early detection in a low- and middle-income country, where a nationwide cancer screening program is urgently needed but currently not available.

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“…Multi-cancer early detection (MCED) tests can potentially overcome these challenges by simultaneously detecting multiple cancer types from a single test ( Liu et al, 2020 ). Liquid biopsy, an emerging non-invasive approach for MCED, can capture a wide range of tumor features, including cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), exosomes, proteins, mRNA, and metabolites ( Li et al, 2018 ; Nguyen et al, 2022b ). Among them, ctDNA has become a promising biomarker for detecting early-stage cancers because it is a carrier of genetic and epigenetic modifications from cancer-derived DNA ( Gao et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization

Nguyen

Nguyễn

Doan

et al. 2023

eLife

Self Cite

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Despite their promise, circulating tumor DNA (ctDNA)-based assays for multi-cancer early detection face challenges in test performance, due mostly to the limited abundance of ctDNA and its inherent variability. To address these challenges, published assays to date demanded a very high-depth sequencing, resulting in an elevated price of test. Herein, we developed a multimodal assay called SPOT-MAS (Screening for the Presence Of Tumor by Methylation And Size) to simultaneously profile methylomics, fragmentomics, copy number, and end motifs in a single workflow using targeted and shallow genome-wide sequencing (∼0.55X) of cell-free DNA. We applied SPOT-MAS to 738 nonmetastatic patients with breast, colorectal, gastric, lung and liver cancer, and 1,550 healthy controls. We then employed machine learning to extract multiple cancer and tissue-specific signatures for detecting and locating cancer. SPOT-MAS successfully detected the five cancer types with a sensitivity of 72.4% at 97.0% specificity. The sensitivities for detecting early-stage cancers were 62.3% and 73.9% for stage I and II, respectively, increasing to 88.3% for nonmetastatic stage IIIA. For tumor-of-origin, our assay achieved an accuracy of 0.7. Our study demonstrates comparable performance to other ctDNA-based assays while requiring significantly lower sequencing depth, making it economically feasible for population-wide screening.

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Ultra-Deep Sequencing of Plasma-Circulating DNA for the Detection of Tumor- Derived Mutations in Patients with Nonmetastatic Colorectal Cancer

Cited by 8 publications

References 44 publications

Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization

Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization

Analytical and clinical validation of a circulating tumor DNA-based assay for multi-cancer early detection

Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization

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