INTERNATIONAL CONGRESS OF
CancerGenetics
Epigenetic Memory in Hereditary Cancers: Bridging Germline Mutations, Somatic Evolution, and Synthetic Therapeutic Vulnerabilities
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Reyhaneh Ashjari Aghdam ,1,*
1. Department of Cellular and Molecular Biology, Faculty of Basic Sciences, Islamic Azad University, Tabriz Branch, Tabriz, Iran.
- Introduction: Waddington's epigenetic memory is heredity of stable patterns of long-term gene expression in cell divisions without DNA alteration and has implications for cancer initiation. Inherited cancers (5–10% of all cancers) arise due to germline mutations in genes like BRCA1/2, TP53, and MMR genes (e.g., MLH1), implicated in syndromes like hereditary breast and ovarian cancer (HBOC) and Lynch syndrome. These mutations damage DNA repair and interact with epigenetic processes, resulting in carcinogenesis. Epigenetic marks, like CpG island hypermethylation and histone (e.g., H3K27me3) changes, more often than not antecedent to genetic changes, silence tumor suppressors. In hereditary settings, hypomethylation due to BRCA1 mutations generates genomic instability. Somatic evolution exploits epigenetic flexibility, creating heterogeneity and resistance. Synthetic vulnerabilities, like PARP inhibitor sensitivity in BRCA-deficient cells, are the consequence of these processes. Despite TCGA achievements, epigenetic contribution is comparatively underresearched. Through this review, epigenetic memory's role in connecting germline mutation, somatic evolution, and therapy in hereditary cancers is brought together.
- Methods: According to the PRISMA guideline, a search of PubMed, Scopus, and Web of Science (2010–July 2025) was conducted using the terms "epigenetic memory AND hereditary cancer" and "synthetic lethality AND epigenetics." The inclusion criteria were English peer-reviewed publications and reviews concerning epigenetic mechanisms, germline-somatic interfaces, and therapy in hereditary cancers. Exclusion criteria were non-human publication and abstracts. Out of 1,000 screened articles, 300 were obtained as full text and 80 were shortlisted following quality appraisal by AMSTAR-2 for reviews and Newcastle-Ottawa for observational studies. Study design, epigenetic biomarkers, and clinical relevance were extracted in duplicate by two reviewers and any disagreements agreed upon by consensus. Top-impact journals (e.g., Nature Reviews Cancer) were selected to minimize bias.
- Results: 1. Epigenetic Mechanisms Underlying Memory in Cancer Epigenetic memory repairs gene expression by DNA methylation (e.g., DNMT-induced p16INK4a promoter silencing) and histone modification (e.g., EZH2-directed H3K27me3). Non-coding RNAs like XIST establish 3D chromatin structure. Pioneer factor mitotic bookmarking (e.g., FOXA1) maintains inheritance, and transgenerational effects are observed in famine cohort studies correlating methylation with cancer risk. Dysregulation entails epigenetic drift during aging and oncometabolites (e.g., IDH-induced 2-hydroxyglutarate) inducing hypermethylation. 2. Germline Mutations in Hereditary Cancers: Epigenetic Interfaces Germline BRCA1/2 mutations (80% risk of breast/ovarian cancer), MMR gene (Lynch syndrome), and TP53 (Li-Fraumeni) lead to malignancy predisposition. Loss of BRCA1 leads to subsequent instability and hypomethylation, with cis-regulatory consequences on enhancers. Epimutations like MLH1 hypermethylation are mimics of the germline. Intergenerational memory is illustrated in models (e.g., vinclozolin-induced methylation) and studies of paternal age. 3. Somatic Evolution: Epigenetic Drivers of Tumor Heterogeneity and Progression Somatic evolution is by clonal selection and metastatic bottlenecks. Epimutations, like IDH1/2-induced hypermethylation, drive progression, whereas reprogramming enables resistance. Germline mutations (e.g., BRCA1) compel forced somatic evolution through defects in repair and deranged chromatin regulation. 4. Synthetic Therapeutic Vulnerabilities: Exploitation of Epigenetic Memory Synthetic lethality is reversing dependencies, for example, PARP inhibitors in BRCA-deficient cancer and EZH2 inhibitors in SWI/SNF mutants. Inhibitors of DNMT (azacitidine) and HDAC (vorinostat) reverse epigenetic changes and combinations with immunotherapies are superior. CRISPR screens and AI reveal novel vulnerabilities but trials are burdened by off-target and biomarker problems.
- Conclusion: Epigenetic memory unites germline predispositions with somatic evolution to reveal synthetic vulnerabilities for precision therapy of hereditary cancer. Limitations are heterogeneity of assays and ethics of germline editing. Future uses are spatial epigenomics and epi-CRISPR to drive precision oncology.
- Keywords: Epigenetic memory; Hereditary cancers; Germline mutations; Somatic evolution; Synthetic lethality
