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INTERNATIONAL CONGRESS OF

CancerGenetics

• The Role of Promoter Hypermethylation in BRCA1/2 Mutation Carriers and the Risk of Triple-Negative Breast Cancer

• Ali kohyarnejadfard,¹ Asma yazdani,² Pouya Salehipour,^3,*
  1. Student Research Committee,Tehran University of Medical Sciences, Tehran, IR Iran
  2. Student Research Committee, Ahvaz Jondishapur University of Medical Sciences, Ahvaz, IR Iran
  3. Tehran University of Medical Sciences, Tehran, IR Iran
  
  
  
• Introduction: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with a poor prognosis, accounting for approximately 10–15% of all breast cancer cases. It is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression. Studies indicate that 10–20% of TNBC patients carry germline mutations in the BRCA1 or BRCA2 genes. These mutations are a major cause of homologous recombination (HR) repair deficiency and play a key role in TNBC pathophysiology. However, even in the absence of BRCA mutations, epigenetic alterations such as BRCA1 promoter hypermethylation can lead to gene silencing and disruption of double strand DNA repair. Evidence from human tumor samples suggests that this epigenetic change is more prevalent than pathogenic BRCA1 mutations and exerts similar molecular effects, being associated with genomic instability and greater tumor aggressiveness. Such epigenetic inactivation functions analogously to BRCA mutations and may contribute to the initiation and progression of TNBC. Given the reported association between BRCA1/BRCA2 promoter hypermethylation, DNA repair deficiency, and TNBC progression, a comprehensive review is warranted to consolidate existing data and assess these alterations as potential diagnostic and prognostic biomarkers. Accordingly, the aim of this study was to systematically review the literature on the role of these epigenetic changes and their association with TNBC risk.
• Methods: This systematic review was conducted according to the PICO framework and the PRISMA checklist. A comprehensive literature search covering publications from 2020 to 2025 was performed in PubMed, SCOPUS, Web of Science, SID, Magiran, and Google Scholar using Boolean operators and MeSH keywords including "Promoter Hypermethylation," "Triple-Negative Breast Cancer," "BRCA1," and "BRCA2." Two independent researchers screened the retrieved studies based on predefined inclusion criteria. Following critical appraisal and application of inclusion and exclusion criteria, 9 articles were selected from an initial pool of 145 studies.
• Results: BRCA1 promoter hypermethylation is recognized as a significant risk factor for breast cancer, particularly among young women, and may serve as an early biomarker for TNBC, a subtype characterized by rapid growth, high invasiveness, and early metastasis. Compared with pathogenic BRCA1/BRCA2 mutations, which account for only about 25% of familial breast cancer cases, this epigenetic alteration shows a higher prevalence. A significant association was observed between BRCA1 promoter hypermethylation and more advanced stages of breast cancer at diagnosis (χ² = 4.31, p = 0.038). Patients with this epigenetic change were more than four times as likely to present with metastatic or advanced disease (OR = 4.04; 95% CI: 1.19–13.65). This finding is statistically robust, although the wide confidence interval suggests possible limitations due to small sample size or data variability. Furthermore, the alteration was more common among patients without a family history of breast cancer.
• Conclusion: This study demonstrates a significant association between BRCA1 promoter hypermethylation and the progression and metastasis of TNBC. Detection of this epigenetic alteration, particularly when combined with anticancer agents such as PARP inhibitors, holds substantial potential for the development of targeted and personalized therapies. Environmental stressors including exposure to carcinogenic chemicals, industrial pollutants, and ionizing radiation appear to contribute to the development of these epigenetic changes in TNBC patients, influencing disease progression and aggressiveness. Given the critical role of BRCA1 promoter hypermethylation in TNBC progression, the development and implementation of sensitive and early detection methods, such as methylation-specific PCR (MSP) and bisulfite sequencing, are essential. Future research should focus on elucidating the underlying epigenetic mechanisms and advancing the identification of precise biomarkers to inform novel therapeutic strategies for TNBC patients
• Keywords: Promoter Hypermethylation / BRCA1 / BRCA2 / Triple-Negative Breast Cancer