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Background <p>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.</p> Results <p>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 <i>GPR126</i>, <i>KLF3</i>, and <i>TLR10</i> and hypomethylation in <i>TOP1</i> and <i>MAFB</i>. 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.</p> Conclusions <p>These findings underscore the potential of cfDNA biomarkers to enhance BC detection and reduce the rate of unnecessary biopsies.</p>

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Multimodal analysis of cell-free DNA enhances differentiation of early-stage breast cancer from benign lesions and healthy individuals

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月20日

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  • 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

摘要

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.