INTERNATIONAL CONGRESS OF
CancerGenetics
Epigenetic Alterations in Hereditary Cancers: Mechanisms, Biomarkers, and Therapeutic Advances
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Javad Fazeli,1 Maryam Shirmohamadi,2 Mohamadhasan Sheikhha,3,*
1. Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
2. Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
3. Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Introduction: Introduction: Hereditary cancers account for 5–10% of all malignancies and are usually associated with germline mutations in tumor suppressor genes such as BRCA1/2, MLH1, MSH2 and APC. However, there is increasing evidence that these inherited mutations are often associated with epigenetic changes, i.e., heritable but reversible modifications that regulate gene expression without altering the DNA sequence. Epigenetic mechanisms such as DNA methylation, histone modifications and non-coding RNA activity can silence tumor suppressor genes or activate oncogenes. This review examines how these epigenetic modifications contribute to hereditary cancers and explores their utility as diagnostic biomarkers and therapeutic targets.
- Methods: Methods: A literature search was conducted in databases such as PubMed, Google Scholar and ScienceDirect, focusing on articles published between 2020 and 2025. Search terms included epigenetics, hereditary cancer, BRCA1 methylation, Lynch syndrome epigenetics, non-coding RNAs in cancer and epigenetic therapies. Only peer-reviewed original studies and systematic reviews in English were considered. Over 80 publications were screened, of which 30 of the most relevant and recent were selected for this review, focusing on clinical and molecular findings applicable to hereditary cancer syndromes.
- Results: Results: 1. DNA methylation in hereditary cancer syndromes Hypermethylation of the BRCA1 promoter was observed in familial breast and ovarian cancer without BRCA1 mutations. Hypermethylation of the MLH1 or MSH2 genes is also a common secondary event in Lynch syndrome, leading to microsatellite instability, even in individuals with intact gene sequences. 2. Histone modifications and chromatin remodeling Aberrant histone methylation and acetylation have been associated with transcriptional silencing in familial colorectal and gastric cancer. Loss of H3K27me3 and overexpression of histone-modifying enzymes such as EZH2 have been detected in tumor tissues from BRCA mutation carriers. 3. Non-coding RNAs and RNA modifications Micro-RNAs (e.g. miR-34a, miR-155) and long non-coding RNAs are frequently dysregulated in hereditary cancers and affect apoptosis, DNA repair and proliferation pathways. Recently, m6A RNA methylation has been proposed as a level of post-transcriptional epigenetic regulation that contributes to hereditary tumor progression. 4. Biomarkers and therapeutic potential Genome-wide methylation profiling has identified epigenetic signatures that distinguish hereditary cancer patients from sporadic cases. Epigenetic therapies, including DNMT inhibitors (e.g. azacitidine) and HDAC inhibitors, have entered clinical trials with promising results, particularly in BRCA-related cancers and mismatch repair deficient tumors.
- Conclusion: Conclusion: Epigenetic mechanisms are increasingly recognized as key factors in the development and progression of hereditary cancers. While germline mutations form the basis for inherited susceptibility, epigenetic changes modulate gene expression patterns, tumor heterogeneity and response to therapy. The dynamic and reversible nature of these changes makes them ideal candidates for diagnostic and therapeutic intervention. Future research integrating genetic and epigenetic profiles will be crucial for improving early detection, risk prediction and personalized treatment in hereditary cancer syndromes.
- Keywords: Keywords: Epigenetics, Hereditary cancer, DNA methylation, BRCA1, Lynch syndrome, Biomarkers, Non-co
