Author:
Nguyen Van Thien Chi,Nguyen Trong Hieu,Doan Nhu Nhat Tan,Pham Thi Mong Quynh,Nguyen Giang Thi Huong,Nguyen Thanh Dat,Tran Thuy Thi Thu,Vo Duy Long,Phan Thanh Hai,Jasmine Thanh Xuan,Nguyen Van Chu,Nguyen Huu Thinh,Nguyen Trieu Vu,Nguyen Thi Hue Hanh,Huynh Le Anh Khoa,Tran Trung Hieu,Dang Quang Thong,Doan Thuy Nguyen,Tran Anh Minh,Nguyen Viet Hai,Nguyen Vu Tuan Anh,Ho Le Minh Quoc,Tran Quang Dat,Pham Thi Thu Thuy,Ho Tan Dat,Nguyen Bao Toan,Nguyen Thanh Nhan Vo,Nguyen Thanh Dang,Phu Dung Thai Bieu,Phan Boi Hoan Huu,Vo Thi Loan,Nai Thi Huong Thoang,Tran Thuy Trang,Truong My Hoang,Tran Ngan Chau,Le Trung Kien,Tran Thanh Huong Thi,Duong Minh Long,Bach Hoai Phuong Thi,Kim Van Vu,Pham The Anh,Tran Duc Huy,Le Trinh Ngoc An,Pham Truong Vinh Ngoc,Le Minh Triet,Vo Dac Ho,Tran Thi Minh Thu,Nguyen Minh Nguyen,Van Thi Tuong Vi,Nguyen Anh Nhu,Tran Thi Trang,Tran Vu Uyen,Le Minh Phong,Do Thi Thanh,Phan Thi Van,Nguyen Luu Hong Dang,Nguyen Duy Sinh,Cao Van Thinh,Do Thanh Thuy Thi,Truong Dinh Kiet,Tang Hung Sang,Giang Hoa,Nguyen Hoai Nghia,Phan Minh Duy,Tran Le Son
Abstract
AbstractDespite 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.
Publisher
Cold Spring Harbor Laboratory