INTERNATIONAL CONGRESS OF
CancerGenetics
Epigenetic Alterations in Hereditary Cancers: Diagnostic, Prognostic, and Therapeutic Insights
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Sheida Khajeh Talkhouncheh,1,*
1. Azad University of Najafabad , Isfahan , Iran
- Introduction: Epigenetics involves heritable changes in gene expression without altering the DNA sequence. This process is mainly driven by DNA methylation, histone modifications, and non-coding RNAs. These mechanisms play a key role in regulating cell growth, differentiation, programmed cell death, and DNA repair. Unlike genetic mutations, epigenetic changes can be reversed, creating unique opportunities for treatment. In hereditary cancers, epigenetic changes interact with germline mutations, such as BRCA1/2 and MMR genes. This interaction can influence how likely a person is to develop the disease, as well as when it may begin and how it progresses. Secondary epimutations can silence tumor suppressor genes in families without obvious mutations. This highlights the importance of including epigenetic profiling in diagnostics, risk assessment, and treatment planning. Additionally, epigenetic markers can affect tumor aggressiveness, chance of recurrence, and response to treatment, showing their clinical importance beyond genetics alone.
- Methods: This narrative review brings together studies on epigenetic changes in hereditary cancers, focusing on DNA methylation, histone modifications, non-coding RNAs, and constitutional secondary epimutations. We looked at detection methods like high-throughput sequencing (NGS, bisulfite sequencing, ChIP-seq, and long-read sequencing), PCR-based tests, microarrays, and non-invasive liquid biopsy platforms for clinical and research uses. We examined case studies in hereditary breast cancer (BRCA1/2), Lynch syndrome, hereditary neuroendocrine tumors (NETs), and hereditary gastric cancer to show their diagnostic, prognostic, and treatment implications. We also reviewed epigenetic drugs, combination therapies, immune-epigenetic interactions, and new bioinformatics and AI-driven methods to assess strategies for personalized medicine.
- Results: Types of Epigenetic Alterations: DNA Methylation: Increased methylation of tumor suppressor genes, like BRCA1 and MLH1, contributes to cancer development without relying on germline mutations. Inherited secondary epimutations driven by cis-acting variants show an inherited epigenetic risk. Histone Modifications: Changes in acetylation, methylation, and phosphorylation affect chromatin structure and gene expression. Certain patterns link to tumor aggressiveness and survival rates. Non-coding RNAs: Disrupted miRNAs and lncRNAs affect cell growth, programmed cell death, and DNA repair. Circulating miRNAs serve as non-invasive biomarkers for monitoring prognosis and therapy. Molecular Mechanisms: Cis-acting genetic variants can cause secondary epimutations, which lead to the silencing of tumor suppressors. Interactions between germline mutations and epigenetic changes lead to tumor diversity and complex traits. Epigenetic profiles categorize patients by risk and help predict treatment response. Diagnostic Implications: High-throughput sequencing, PCR, and microarrays enable accurate detection of methylation and ncRNA changes. Liquid biopsy platforms and saliva sampling allow non-invasive detection of circulating tumor DNA and extracellular vesicles with epigenetic markers. Combining epigenetic data enhances early detection, patient classification, and recognition of mutation-negative hereditary cancer cases. Prognostic Value: Epigenetic signatures can predict the chances of recurrence, disease progression, and survival. Histone modification patterns and circulating miRNAs link to tumor aggressiveness and responses to therapy. Personalized risk models that include epigenetic information work better than those that only consider genetic mutations. Therapeutic Implications: Current Drugs: DNMT inhibitors, such as azacytidine and decitabine, block CpG island methylation, reactivating silenced tumor suppressors. HDAC inhibitors increase histone acetylation, which boosts the transcription of genes that cause cell growth arrest and apoptosis. Emerging Targets: Histone methyltransferases, demethylases, bromodomain-containing proteins, and chromatin remodelers present selective opportunities for intervention. Combination Therapies: Pairing epigenetic agents with immunotherapies, targeted therapies, or chemotherapy enhances effectiveness, overcomes resistance, and alters the tumor environment. Challenges: Off-target effects, therapy resistance, and toxicity pose challenges. New drug delivery methods, CRISPR/dCas9-based epigenetic editing, and AI-driven biomarker identification aim to improve accuracy and results. Case Studies: Breast Cancer (BRCA1/2): Increased methylation and histone modifications affect gene expression. Male breast cancer and triple-negative subtypes have distinct epigenetic profiles that require integrated analysis for personalized treatment. Lynch Syndrome: MLH1 promoter hypermethylation can lead to defective mismatch repair and microsatellite instability. Epigenetic profiling helps with detection and monitoring. Other Cancers: Hereditary neuroendocrine tumors feature mutations in chromatin remodeling genes and widespread methylation. Hereditary diffuse gastric cancer associated with CDH1 mutations shows epigenetic silencing of E-cadherin, affecting disease progression and outlook. Detection Techniques: High-throughput sequencing (NGS, ChIP-seq, bisulfite, long-read ONT). PCR methods (qPCR, droplet digital PCR) and microarrays. Non-invasive biomarker detection through liquid biopsies and saliva sampling, supporting multi-omics integration. Epigenetics and Immune Evasion: DNA methylation and histone modifications control checkpoint expression, antigen presentation, and cytokine profiles. Epigenetic drugs improve the effectiveness of immunotherapy by increasing tumor antigen expression and immune cell infiltration. Integrative Personalized Medicine: Combining genetic and epigenetic information enhances risk classification, therapy choice, and early intervention. AI and bioinformatics facilitate multi-omics integration, discovery of biomarkers, and accurate prognosis modeling.
- Conclusion: Epigenetic changes play a key role in hereditary cancer development. They impact diagnosis, prognosis, and treatment. Improvements in profiling technologies, finding biomarkers, and creating epigenetic therapies, including those that work with immunotherapies, support personalized cancer care. Combining epigenetic and genetic information allows for tailored risk assessment, treatment selection, and preventive measures. Future research should focus on long-term studies, single-cell analysis, resistance mechanisms, and combining different types of data. Working together across various fields is important to apply these findings in clinical practice and enhance outcomes for patients with hereditary cancer.
- Keywords: Hereditary Cancer, Epigenetics, DNA Methylation, Histone Modifications, Non-coding RNA, Secondary Ep
