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INTERNATIONAL CONGRESS OF

CancerGenetics

• Histone Dysregulation and Hereditary Cancer Syndromes

• Maryam Radmanfard,^1,* Asal Naghipour_Kordlar,²
  1. Department of Basic Sciences, Ta.C., Islamic Azad University, Tabriz, Iran
  2. Faculty of Nursing, Tabriz University of Medical Sciences, Tabriz, Iran
  
  
  
• Introduction: 1.1. The Epigenetic World of Cancer: Beyond the Genome The etiology of cancer, once considered through the lens of genetic mutations, is today known to reflect an intricate interplay between the genome and the epigenome. Epigenetics describes heritable changes in gene expression that are not encoded within the primary DNA sequence but stably propagated through cell division. These processes offer a dynamic regulatory layer that interprets the static genetic code and programs the various expression programs necessary for normal development and cellular identity. If the DNA sequence can be equated with the hardware of the computer, the epigenome more accurately can be described as the software that determines which programs are executed, when, and where. In cancer, the software is corrupted. Global changes within the epigenetic landscape, such as aberrant DNA methylation, histone modifications, and non-coding RNA expression, are increasingly acknowledged as a universal characteristic of the process of malignant transformation. This conceptual shift was formally acknowledged through the addition of non mutational epigenetic reprogramming as a new characteristic of cancer as one of the hallmarks, concretely establishing the epigenome as a key player within the process of carcinogenesis (Khan et al., 2025). 1.2. Histone Modifications at the Center of Regulation Centerpiece of epigenetic regulation is the chromatin fiber, an orderly complex of DNA and proteins within the eukaryotic nucleus. Its basic repeating unit, the nucleosome, is composed of about 147 base pairs of DNA coiled around an octamer of histone proteins (two subunits each of H2A, H2B, H3, and H4). This compaction creates a physical obstacle in the way of the transcriptional machinery, and dynamic regulation of chromatin conformation plays a critical role in gene regulation. The principal mechanism for such regulation is the post-translational modification (PTM) of histones, especially on their extended N-terminal tails that project outward from the core of the nucleosome. A vast array of covalent modifications, such as acetylation, methylation, phosphorylation, and ubiquitination, can be deposited on or removed from particular amino acid residues on the histone tails. These PTMs serve as an advanced signaling platform, modifying histone-DNA interaction and recruiting specific effector proteins to establish an overall chromatin environment, either permissive (euchromatin) or repressive (heterochromatin), to transcription (Kumagai et al., 2025). 1.3. Hereditary Cancer Syndromes: The Germl Although the vast majority of cancers develop through an accumulation of somatic mutations, an estimated 5-10% are the result of hereditary cancer syndromes (HCS). HCS are inherited conditions resulting from pathogenic versions of a single cancer predisposition gene that are passed down through the generations in an autosomal dominant manner. When such a version is inherited, the individual develops at markedly increased risk throughout their lifetime of specific types of cancer, typically at an early age. Knudson's two-hit hypothesis has been the classic model of tumorigenesis for HCS. The first hit is the inherited germline mutation, present within all the body's cells. An initiation of the cancer requires the occurrence of a second hit i.e., a somatic mutation or loss of the last intact (wild-type) allele—in one of the target susceptibility tissues, whereby the tumor suppressor is completely lost and tumor development results. In the present review, we shall consider three of the best-characterized HCS: the Hereditary Breast and Ovarian Cancer (HBOC) syndrome, resulting from germline mutations in BRCA1 and BRCA2; Lynch syndrome owing to mutations within the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2); and Li-Fraumeni syndrome owing to TP53 master tumor suppressor gene mutations (Wang et al., 2025). 1.4. Review Aims and Scope: Relating Histone Patterns and Inherited Risk for Cancer HCS studies traditionally emphasized the classical tumor suppressor activities of their related genes, i.e., DNA repair (BRCA1/2, MMR genes) or cell cycle regulation (TP53). Nevertheless, an increasingly evident undercurrent describes an intimate relationship: the protein product of these key HCS genes is not an innocent bystander within the epigenetic drama but an active player and director of the epigenetic machine itself. Understood broadly, the unifying argument of this review is that germline mutations of these genes trigger predictable and functionally relevant changes to the histone modification landscape. These changes are not downstream consequences of genome instability but are more often primary causative events establishing an epigenetic configuration conducive to tumorigenesis. In the present work, we systematically disassemble the process whereby the loss-of-function or gain-of-function character of these germline mutations maps onto specific histone acetylation, methylation, and ubiquitylation patterns. In studying the characteristic epigenetic signatures for HBOC, Lynch, and Li-Fraumeni syndrome, we strive for an integration of inherited genetic risk and the epigenetic dysregulation driving cancer and wish to point the way toward novel therapeutic strategies for the latter (Webster & Phillips, 2025).
• Methods: This systematic review integrates literature identified through a systematic search of the PubMed/MEDLINE, Scopus, and Web of Science databases through 2025. The search strategy used a combination of free-text terms and Medical Subject Headings (MeSH) descriptors, including histone modification, epigenetics, hereditary cancer syndrome, epimutation and epigenetic therapy. These were cross-referenced with syndrome-specific descriptors such as Hereditary Breast and Ovarian Cancer, Lynch Syndrome, Li-Fraumeni Syndrome, and their corresponding genes (BRCA1, BRCA2, MLH1, MSH2, TP53). Additional searches utilized descriptors for enzymes and drugs including specific ones for the EZH2, the HDAC inhibitor and the PARP inhibitor (Webster & Phillips, 2025). English peer-reviewed original research articles, comprehensive reviews, and published clinical trial reports were considered for selection. Non-peer reviewed materials such as conference abstracts where the full publication does not exist were excluded. Great importance was given to studies that employed the genome-wide approaches such as Chromatin Immunoprecipitation followed by Sequencing (ChIP-Seq), which provide high resolution data on the deposition of the histone modifications.
• Results: 3.1. The Histone Code and Its Disregulation in Cancer The Hist, It is regulated by enzymes that are assigned the classification of writers (e.g., HATs, HMTs), erasers (e.g., HDACs, KDMs), and readers that identify these marks. They affect transcription either by modifying chromatin architecture or by providing docking sites for regulatory proteins. As an example, histone acetylation consistently produces an open chromatin configuration conducive to transcription, whereas marks such as H3K27 trimethylation are involved in gene suppression. Cancer is the consequence of an extreme disruption of epigenetic control and is typically associated with the suppression of tumor suppressor genes by the combined effect of DNA hypermethylation and histone deacetylation (Wang et al., 2025). 3.2. Histone Modification for Hereditary Breast and Ovarian Cancer (HBOC The BRCA1 product thus not only functions in DNA repair but also acts directly as an epigenetic regulator via E3 ubiquitin ligase function and via recruitment of the HDACs into gene promoters. In HBOC, germline inactivation of BRCA1 adversely affects these actions, leading to aberrant histone modifying profiles and genomic instability. Another key consequence of the destruction of BRCA1 is the overexpression of the histone methyltransferase EZH2, the PRC2 (Polycomb Repressive Complex 2) catalytic subunit. Hyperactivity of the latter leads to elevated global levels of the repressive H3K27me3 mark, resulting in the inhibition of cellular differentiation genes and the facilitation of the aggressive phenotype of BRCA1-mutated tumors (Pitt et al., 2025). 3.3. Epigenetic Changes of Lynch Syndrome While Lynch Syndrome (LS) typically arises from germline mutations of mismatch repair (MMR) genes, a tiny percentage arises from an apparently pure epigenetic process, i.e., constitutional epimutation. It is a paradigm of CpG island hypermethylation of one First-hit MLH1 gene promoter within the normal tissues of an individual, forming a functional first hit by suppressing the allele via a repressive state of chromatin. In spite of the initiating factor, MMR deficiency leads to hypermutated tumors that are very apparent to the immunological surveillance system. They can exploit epigenetic silencing mechanisms, for example, the histone methyltransferase EZH2, for the purpose of silencing immune-related genes and thus allowing for immune evasion (Shah et al., 2025). 3.4. Epigenetic Consequences of TP53 Mutation for Li-F p53 wild-type protein acts as guardian of epigenetic stability by recruiting various histone-modifying enzymes for its target genes. In contrast, the vast TP53 mutations for Li-Fraumeni Syndrome (LFS) are missense mutations that produce a mutant protein with novel cancer-developing (oncogenic) activities, referred to as gain-of-function (GOF). A primary mechanism of GOF is the hijacking of the cell's epigenetic machinery. GOF mutant p53 proteins directly stimulate the expression of genes for key writer enzymes, like the histone methyltransferases MLL1 and MLL2 and the histone acetyltransferase MOZ. This leads to a global increase of activating histone modifications, such as H3K4 methylation and H3K9 acetylation, and activates a global pro-proliferative and metastatic gene program characteristic of LFS (Suraweera et al., 2025). 3.5. Therapeutic Targeting of the Epigenome in Inherited Cancers Since epigenetic changes are reversible, these are promising targets for cancer therapy. Epi drugs like HDAC inhibitors (HDACi) try to reverse the disrupted histone code that governs cancer. Another promising approach is the establishment of a state of BRCAness for the purpose of establishing synthetic lethality. PARP inhibitors are very effective within tumors with faulty DNA repair, like those with BRCA1/2 mutations. In tumors with functional BRCA proteins, HDAC inhibitors can be used to transcriptionally suppress DNA repair genes, inducing a pharmacological BRCA-deficient state. This acquired vulnerability renders the cancer cells highly sensitive to PARP inhibitors, and the combination has shown powerful synergistic anti-tumor activity in preclinical models (Ma et al., 2025).
• Conclusion: 4.1. Integrating the Histone Modification Patterns Within the Main Hereditary Cancer Syndromes The confluence of germline genetics and epigenetics in HCS provides a spectrum of molecular pathologies centered upon the dysregulation of the histone code. This review has integrated the evidence showing that the principal HCS are not simply diseases of DNA repair or cell cycle control but are actually diseases of epigenetic dysregulation. The mechanism of the dysregulation is different for each syndrome. In HBOC, the responsible gene product, BRCA1, is a direct player within the epigenetic machine, serving as a histone E3 ubiquitin ligase and recruiter of HDACs, such that its loss results in a failure of epigenetic control by default. In Lynch Syndrome, a primary epigenetic lesion constitutional MLH1 promoter hypermethylation perfectly mimics a genetic first-hit and initiates the cascade for tumorigenesis through histone-mediated gene silencing. In Li-Fraumeni Syndrome, the paradigm shifts again such that the mutated p53 protein is not lost but reprogrammed into a neomorphic oncogene protein that actively co-opts and re-wires the epigenetic machine through the upregulation of pivotal histone methyl- and acetelyltransferases. These different mechanisms direct participation, genetic mimicry, and active co-option highlight the complex and context-dependent ways that the germline genome and the epigenome deploy and trigger hereditary cancer (Ji et al., 2025). 4.2. Determining Knowledge Gaps and Future Needs for Research Despite the profound advances in this field, significant knowledge gaps remain. Future research must be directed towards several key imperatives to translate these mechanistic insights into clinical benefits. First, there is a critical need for high-resolution, multi-omic mapping of the complete histone code, integrating data on different PTMs, DNA methylation, and transcriptomics. Tracking the evolution of this code from pre-cancerous lesions through primary tumors to metastatic disease in large cohorts of HCS patients will be essential for understanding tumor progression and identifying early intervention points. Second, the full spectrum of non-histone protein targets of the epigenetic enzymes dysregulated in HCS remains largely unexplored and represents a major gap in our understanding. Third, as epi-drugs become more widely used, elucidating the molecular mechanisms of both primary and acquired resistance is paramount for developing next-generation agents and rational combination strategies. Finally, the intricate cross-talk between the tumor cell's epigenome and the cells of the tumor microenvironment, particularly immune cells, is a burgeoning area of research. Understanding how the epigenetic landscape in HCS tumors shapes, and is in turn shaped by, the immune response will be crucial for the successful integration of epigenetic therapies with immunotherapy (Khan et al., 2025). 4.3. Translational Perspective Transforming Mechanistic Understanding into Clinical The increasing appreciation of the patterns of histone modification in HCS is driving the field forward from descriptive biology toward the derivation of practical clinical strategies. The built-in reversibility of the epigenome offers an attractive therapeutic window that is currently being taken advantage of by an expanding armament of epi-drugs. The future of cancer therapy for patients with HCS is precision epigenetic medicine. This will entail the utilization of stable epigenetic biomarkers, such as particular histone modification signatures or the degrees of expression of key enzymes such as EZH2, for the purpose of dividing patients into subgroups and for the direction of treatment choices. The augmentation and elaboration of very specific next-generation inhibitors and the conceptualization of clever combination therapies, such as the synergistic combination of the HDAC and PARP inhibitors for the purpose of creating BRCAness, are the frontier extremes of such a method of treatment. Through the ongoing unwinding of the intricately complex language of the histone code and the manner by which it is subverted by germline mutations, we can more efficiently make use of the very specific epigenetic vulnerabilities of hereditary cancers, and promise the derivation of more effective and personalized therapies for these high-risk patients (Ma et al., 2025).
• Keywords: Histone Modification, Epigenetics, Hereditary Cancer Syndromes, BRCA1, Lynch Syndrome.