Circulating cell-free DNA-based methylation patterns for breast cancer diagnosis

Area of Science:

• Oncology
• Genomics
• Biomarkers

Background:

• Mammography has limitations in breast cancer (BC) detection, particularly in women with dense breasts.
• Circulating cell-free DNA (cfDNA) methylation tests are emerging as a potential tool to enhance BC diagnosis.

Purpose of the Study:

• To develop and validate a cfDNA methylation-based diagnostic prediction model for breast cancer.
• To compare the diagnostic performance of the cfDNA methylation model against mammography.

Main Methods:

• Computational analysis of DNA methylation profiles from The Cancer Genome Atlas (TCGA) to identify candidate markers.
• Development and validation of a 26-marker cfDNA methylation panel and a simplified 4-marker model.
• Independent testing of the model on a separate dataset and comparison with mammography's diagnostic power.

Main Results:

• The 26-marker cfDNA methylation model achieved high sensitivity (89.37%) and specificity (100%) in initial validation.
• A simplified 4-marker model and a single marker (cg23035715) also showed significant diagnostic power.
• The cfDNA methylation model demonstrated superior diagnostic performance (AUROC=0.9815) compared to mammography (AUROC=0.9315) in an independent test set.
• Hypermethylation profiling provided insights into lymph node metastasis stratification.

Conclusions:

• A cfDNA methylation-based model has been developed and validated for breast cancer diagnosis.
• This cfDNA methylation test offers improved diagnostic accuracy over mammography.
• The findings suggest cfDNA methylation analysis is a promising approach for non-invasive BC detection and potentially for assessing metastasis risk.