BMC Biol. 2025 Aug 20. 23(1): 259
Thi Tuong Vi Van,
Trung Hieu Tran,
Thi Hue Hanh Nguyen,
Van Thien Chi Nguyen,
Dac Ho Vo,
Giang Thi Huong Nguyen,
Trong Hieu Nguyen,
Kim Sang To,
Anh Luan Nguyen,
Cao Hong An Tran,
Thanh Xuan Jasmine,
Thi Loan Vo,
Thi Huong Thoang Nai,
Thuy Trang Tran,
My Hoang Truong,
Ngan Chau Tran,
Thi Loc Le,
Thi Hong Nhung Nguyen,
Ngoc Hieu Tu,
Thanh Son Tran,
Bao Toan Le,
Van Phong Tang,
Pham Thanh Nhan Nguyen,
Khac Tien Nguyen,
Van Chien Ho,
Xuan Vinh Nguyen,
Nhu Nhat Tan Doan,
Thi Trang Tran,
Thi Minh Thu Tran,
Vu Uyen Tran,
Minh Phong Le,
Thi Luyen Vu,
Ba Linh Tieu,
Huu Tam Phuc Nguyen,
Luu Hong Dang Nguyen,
Ngoc Minh Phan,
Thi Van Phan,
Thi Thanh Thuy Do,
Thi Huyen Dao,
Hung Sang Tang,
Duy Sinh Nguyen,
Hoa Giang,
Minh Duy Phan,
Hoai-Nghia Nguyen,
Duc Hieu Vo,
Le Son Tran.
BACKGROUND: Breast cancer (BC) remains the second leading cause of cancer-related mortality among women worldwide. Liquid biopsy based on circulating tumor DNA (ctDNA) offers a promising noninvasive approach for early detection; however, differentiating malignant tumors from benign abnormalities remains a significant challenge.
RESULTS: Here, we developed a multimodal approach to analyze cfDNA methylation and fragmentomic patterns in 273 BC patients, 108 individuals with benign breast conditions, and 134 healthy controls. Genome-wide analyses revealed distinct cfDNA copy number alterations and cytosine-enriched cleavage sites in BC patients. Targeted sequencing further revealed unique methylation patterns, including hypermethylation in GPR126, KLF3, and TLR10 and hypomethylation in TOP1 and MAFB. Our machine-learning model achieved an AUC of 0.90, with 93.6% specificity and 62.1-66.3% sensitivity for stage I-II cancers. In symptomatic populations, sensitivities were 50.0%, 68.2%, and 64.7% for BI-RADS categories 3, 4, and 5, respectively, with 96.1% specificity.
CONCLUSIONS: These findings underscore the potential of cfDNA biomarkers to enhance BC detection and reduce the rate of unnecessary biopsies.
Keywords: Benign abnormalities; Breast cancer; CfDNA; Methylation and fragmentomic