Early-onset breast cancer is one of the most common malignancies and causes of death among young women, and its incidence is increasing. In the present study, we aimed to investigate the epigenetic modifications of the breast cancer type 1 susceptibility gene (BRCA1) in breast tissues and blood cells derived from women with breast cancer and women without breast cancer. BRCA1 promoter methylation was examined by methylation-specific PCR in 47 breast cancer tissues and in peripheral blood cells derived from 7 breast cancer patients and 73 healthy women. Subse­quently, the methylation status of the BRCA1 promoter was confirmed and analyzed at high resolution by sodium bisulfite genomic sequencing. BRCA1 promoter methylation was detected in 13 primary sporadic breast cancer tissues (27.3%) and in 2 blood cell samples derived from breast cancer patients (28.5%). A strong association (p-value, 0.0038) was found between BRCA1 methylation and young age (≤40 years) at diagnosis. The BRCA1 promoter was also methylated in blood cells from 8 women without breast cancer (10.9%) and 2 breast cancer patients (28%). The methylation pattern of the BRCA1 promoter CpG island was similar in the blood cells from healthy women as well as in women with breast cancer. Moreover, we report for the first time, the observation of methylation-related mutations leading to the formation of non-CpG methylation, as well as the formation of novel methylated CpG sites in the 5' regulatory region of the BRCA1 gene in the peripheral blood cells from cancer-free women. These results suggest the possible implication of BRCA1 promoter methylation in the early onset of breast cancer and propose the use of this epigenetic modification as a powerful molecular marker for detecting women potentially predisposed to cancer.

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