Blood DNA methylation and breast cancer risk: a prospective nested case-control study

Area of Science:

• Genomics and epigenetics
• Cancer research
• Biomarker discovery

Background:

• Mammography screening can be complemented by blood tests predicting breast cancer (BC) risk.
• Whole-blood DNA methylation patterns may indicate early systemic changes related to tumor development.

Purpose of the Study:

• To develop and validate a blood-based DNA methylation risk score (MRS) for predicting breast cancer (BC) risk.
• To assess the performance of the MRS in comparison to existing risk models and polygenic risk scores.

Main Methods:

• Prospective matched case-control study within Sweden's mammography screening program.
• Whole-blood DNA methylation profiling using Illumina MethylationEPIC array.
• Identification and validation of CpG sites to construct a methylation risk score (MRS).

Main Results:

• Identified 22 CpG sites that formed the MRS, significantly associated with BC risk across subtypes.
• MRS performance was comparable to polygenic risk scores and improved 3-5-year prediagnosis discrimination of existing models.
• Association of MRS with BC risk remained stable up to five years pre-diagnosis.

Conclusions:

• A blood DNA methylation signature is significantly associated with BC risk.
• The developed MRS may complement existing models for BC risk stratification, especially for 3-5-year risk estimation.
• Further validation and clinical utility assessment are required.