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Genetic and Epigenetic Analyses in Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 20 April 2026 | Viewed by 7894

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Special Issue Editor

Prof. Dr. Jing Gong

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Guest Editor

College of Informatics, Huazhong Agricultural University, Wuhan, China
Interests: genetics and bioinformatics; multiomics data analysis; biological artificial intelligence

Special Issue Information

Dear Colleagues,

Cancer, as a complex and multifactorial disease, involves profound alterations at both the genetic and epigenetic levels in its pathogenesis. The genetic foundation of cancer encompasses processes such as gene mutations, gene recombination, chromosomal instability, and genetic susceptibility. These genetic alterations can affect critical cellular processes, including proliferation, apoptosis, differentiation, and metabolism, thereby driving cancer progression. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA regulation, provide new insights into the onset and development of complex diseases. Both genetic and epigenetic changes play essential roles in the initiation, progression, and drug resistance of cancer, collectively influencing the disease course. Investigating the roles of these alterations in cancer can enhance our understanding of its complexity and pave the way for more effective therapeutic strategies.

We invite the submission of original research articles, reviews, and opinion pieces on the latest discoveries, theoretical advances, or clinical applications in cancer genetics and epigenetics for this Special Issue. We also seek to explore the interplay between genetic and epigenetic mechanisms in cancer. In particular, we encourage studies that integrate multi-omics approaches, such as combining genetic data with epigenomic, transcriptomic, and proteomic profiles. Our goal is to highlight how genetic and epigenetic analyses can unlock novel cancer biomarkers and therapeutic opportunities.

Prof. Dr. Jing Gong
Guest Editor

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Keywords

epigenetics
genetic mutations
chromosomal instability
DNA methylation
histone modifications
non-coding rnas
multi-omics
transcriptomics
proteomics
drug resistance in cancer
cancer biomarkers
therapeutic targets in cancer

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Published Papers (7 papers)

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Research

Jump to: Review

17 pages, 951 KB

Open AccessArticle

Thyrotropin-Releasing Hormone Gene Methylation as a Potential Biomarker for Anal Intraepithelial Neoplasia

by Chavis Pholpong, Nittaya Phanuphak, Tippawan Pankam, Supranee Buranapraditkun, Nakarin Kitkumthorn, Bernett Lee, Parvapan Bhattarakosol and Arkom Chaiwongkot

Int. J. Mol. Sci. 2025, 26(24), 11784; https://doi.org/10.3390/ijms262411784 - 5 Dec 2025

Viewed by 84

Abstract

Anal cancer is high in men who have sex with men living with human immunodeficiency virus (MSM-LWHIV). This cancer is strongly associated with high-risk human papillomavirus (HR-HPV) infection. Anal cancer screening using cytology and high-resolution anoscopy (HRA) for diagnosis of anal intraepithelial neoplasia requires specialized expertise. Biomarkers for the diagnosis of abnormal anal cells are of interest. Thyrotropin-releasing hormone (TRH) methylation at cg01009664 was detected using a pyrosequencing assay to compare methylation patterns among different anal lesions. Our results demonstrated that TRH methylation was significantly hypermethylated in anal intraepithelial neoplasia (AIN3) (>20%) and AIN1-2 (>10%) but less methylated in normal (<10%) (p < 0.001). TRH gene methylation showed higher sensitivity than the cytology for predicting AIN1+ (75.96% vs. 25.37%, respectively) and AIN2+ (78.95%% vs. 19.23%, respectively). There was no significant correlation between TRH methylation and the percentage of CD4 in patients with HIV (p > 0.05). TRH methylation in anal swabs reflects the presence of anal intraepithelial neoplasia. Methylation analysis showed higher sensitivity than cytology for high-grade lesions and was independent of immune status. These findings support its use as a screening tool to preselect patients for HRA, potentially reducing unnecessary procedures while maintaining diagnostic accuracy. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Analyses in Cancer)

17 pages, 2914 KB

Open AccessArticle

Integrative Epigenomic and Targeted Protein Analysis in MRONJ: Correlating DNA Methylation with Bone Biomarkers

by Raed Awadh Alshammari, Marwa Tantawy, Danxin Wang, Elysse Castro-Hall, Maria Abreu, Alessandro Villa, Joseph Katz, Lexie Shannon Holliday and Yan Gong

Int. J. Mol. Sci. 2025, 26(22), 11208; https://doi.org/10.3390/ijms262211208 - 20 Nov 2025

Viewed by 326

Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse effect of antiresorptive agents, including bisphosphonates (BPs) and denosumab (DMB). We conducted a case–control epigenome-wide association study (EWAS) of 24 cancer patients treated with BPs or BPs + DMB using the Infinium^® MethylationEPIC v2.0 to explore epigenetic differences associated with MRONJ. Differentially methylated positions (DMPs) and regions (DMRs) were assessed across three analyses: MRONJ vs. controls (main), BPs-MRONJ vs. BPs-controls, and BPs/DMB-MRONJ vs. BPs/DMB-controls. Eight plasma bone biomarkers were quantified by Luminex and correlated with top methylation sites. We identified 10 DMPs and 4 DMRs at suggestive significance (p < 1 × 10⁻⁵). cg1913766 in the NOP56 promoter was hypomethylated in the main analysis (p = 2.19 × 10⁻⁷) and in BPs-MRONJ (p = 4.80 × 10⁻⁶), correlating with osteocalcin (p = 0.02 and 0.03, respectively). TNXB cg21289669 was hypermethylated in the main analyses (p = 6.31 × 10⁻⁶), and TNXB locus formed a DMR (p = 3.30 × 10⁻¹⁰) in the main and BPs-MRONJ analyses (p = 2.76 × 10⁻⁷). cg11392877 in PDE8A was hypomethylated in BPs/DMB-MRONJ (p = 5.35 × 10⁻⁷). TRIM15 was a significant DMR in BPs-MRONJ and the main analysis (p = 3.30 × 10⁻¹⁰). TRIM15, TNXB, and PDE8A regulate collagen I, while NOP56 supports ribosome biogenesis, potentially contributing to MRONJ. Given the small sample size, these findings are preliminary and validation in larger studies is warranted. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Analyses in Cancer)

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16 pages, 1324 KB

Open AccessArticle

Identifying Targets and Drugs for Rheumatoid Arthritis Stratified Therapy Using Mendelian Randomization and a Pretraining Model

by Yuqing Yan, You Wu, Yixuan Sun, Tian Wu, Haotian Zhu, Feiyang Xue, Zhanhui Yu, Shichao Liu and Xiaohui Niu

Int. J. Mol. Sci. 2025, 26(12), 5686; https://doi.org/10.3390/ijms26125686 - 13 Jun 2025

Cited by 1 | Viewed by 1207

Abstract

The prevalence of rheumatoid arthritis (RA) subtypes, including seropositive and seronegative, is influenced by lifestyle factors and exhibits high heterogeneity, resulting in reduced drug efficacy. This study aims to identify cytokines mediating the effects of different lifestyles on RA subtypes and to discover new drugs for personalized treatment. Mendelian randomization revealed that three cytokines (MIP1b, SCGFb, and TRAIL) partially mediated the effects of different lifestyles on RA overall or its subtypes. The pretrained model, i.e., DrugBAN, predicted the probability of 723,000 small molecule drugs binding to these three targets. In molecules with high binding rates, we calculated the structural similarity between known drugs for RA and other drugs to screen for new drugs, followed by molecular docking and molecular dynamics simulations for validation. The results indicate that these targets had promising binding affinity with known drugs and other drugs with high similarity. Our findings may guide therapeutic approaches for heterogeneous RA patients with specific lifestyle habits. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Analyses in Cancer)

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19 pages, 2974 KB

Open AccessArticle

Epigenetic Inactivation of RIPK3-Dependent Necroptosis Augments Cisplatin Chemoresistance in Human Osteosarcoma

by Aditya Sharma, Daniel Pettee, Christine Mella, Catherine Hord, Maximilian Brockwell, Samantha Hardy, Hope C. Ball, Fayez F. Safadi and Steven J. Kuerbitz

Int. J. Mol. Sci. 2025, 26(8), 3863; https://doi.org/10.3390/ijms26083863 - 18 Apr 2025

Viewed by 1528

Abstract

Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents. Unfortunately, drug resistance limits the efficacy of chemotherapeutic treatment and compromises therapeutic outcomes in a substantial proportion of cases. Aberrant CpG island methylation-associated transcriptional silencing contributes to chemoresistance in pediatric solid tumors. Here, using whole-genome DNA methylation screening on 16 human primary OS specimens, we identify receptor interacting protein kinase-3 (RIPK3), a molecular regulator of the necroptosis programmed cell death pathway, as a gene target of aberrant CpG methylation and demonstrate its role in human OS chemoresistance. We validated these findings via enforced expression and DsiRNA silencing, and evaluated the role of RIPK3 in cisplatin chemosensitivity and necroptosis activation through MLKL phosphorylation. We found that CpG island methylation results in RIPK3 silencing in primary human OS samples and cell lines. Enforced RIPK3 expression significantly enhanced cisplatin cytotoxicity in OS cells and DsiRNA knockdown reversed the cisplatin-sensitive phenotype. In cells with enforced RIPK3 expression, cisplatin treatment significantly increased phosphorylation of both RIPK3 and its target, MLKL, indicative of induction of necroptosis. Here, we identify RIPK3 as an important mediator of chemoresistance in OS and a potential pharmacologic target to improve chemotherapy efficacy in drug-resistant tumors. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Analyses in Cancer)

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12 pages, 2075 KB

Open AccessArticle

SurvDB: Systematic Identification of Potential Prognostic Biomarkers in 33 Cancer Types

by Zejun Wu, Congcong Min, Wen Cao, Feiyang Xue, Xiaohong Wu, Yanbo Yang, Jianye Yang, Xiaohui Niu and Jing Gong

Int. J. Mol. Sci. 2025, 26(6), 2806; https://doi.org/10.3390/ijms26062806 - 20 Mar 2025

Viewed by 1356

Abstract

The identification of cancer prognostic biomarkers is crucial for predicting disease progression, optimizing personalized therapies, and improving patient survival. Molecular biomarkers are increasingly being identified for cancer prognosis estimation. However, existing studies and databases often focus on single-type molecular biomarkers, deficient in comprehensive multi-omics data integration, which constrains the comprehensive exploration of biomarkers and underlying mechanisms. To fill this gap, we conducted a systematic prognostic analysis using over 10,000 samples across 33 cancer types from The Cancer Genome Atlas (TCGA). Our study integrated nine types of molecular biomarker-related data: single-nucleotide polymorphism (SNP), copy number variation (CNV), alternative splicing (AS), alternative polyadenylation (APA), coding gene expression, DNA methylation, lncRNA expression, miRNA expression, and protein expression. Using log-rank tests, univariate Cox regression (uni-Cox), and multivariate Cox regression (multi-Cox), we evaluated potential biomarkers associated with four clinical outcome endpoints: overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI). As a result, we identified 4,498,523 molecular biomarkers significantly associated with cancer prognosis. Finally, we developed SurvDB, an interactive online database for data retrieval, visualization, and download, providing a comprehensive resource for biomarker discovery and precision oncology research. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Analyses in Cancer)

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Review

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15 pages, 2043 KB

Open AccessReview

Epigenetic and Post-Translational Regulation of Schlafen Family Expression and Their Differential Methods of Regulating Proteins

by Odele Rajpathy and Emilie E. Vomhof-DeKrey

Int. J. Mol. Sci. 2025, 26(22), 11058; https://doi.org/10.3390/ijms262211058 - 15 Nov 2025

Viewed by 478

Abstract

Schlafen (SLFN) proteins are a unique and emerging yet incompletely understood family that have primarily been investigated for their putative roles in immunological responses, cell proliferation, and non-malignant cell differentiation. Increasingly, SLFNs have been implicated in diverse biological and pathological contexts, including cancers, viral replication, embryonic lethality, meiotic drive, and inflammatory bowel diseases, where they may be either genetically upregulated or downregulated. In recent years, novel insights into their functional similarities and distinctive particularities have intensified interest in this gene family. This review critically evaluates the biology of SLFN proteins with a specific focus on the epigenetic regulation of their expression and the differential methods by which they regulate downstream proteins. Evidence indicates that SLFNs act not only as regulators of transcription but also as modulators of gene expression through post-transcriptional modifications and epigenetic mechanisms, which demonstrate their multifaceted and context-dependent activity across disease models. By consolidating these findings, this review brings to light the physiological and pathological significance of SLFNs and identifies key gaps in understanding their epigenetic control and mechanistic diversity, thereby offering directions for future research. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Analyses in Cancer)

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15 pages, 1635 KB

Open AccessReview

Aggressive Thyroid Carcinomas Clinical and Molecular Features: A Systematic Review

by Sorina Schipor, Mihai Alin Publik, Dana Manda and Mihail Ceausu

Int. J. Mol. Sci. 2025, 26(12), 5535; https://doi.org/10.3390/ijms26125535 - 10 Jun 2025

Cited by 3 | Viewed by 2177

Abstract

Aggressive thyroid carcinomas are rare malignancies characterized by a high impact on patient’s lives and poor prognosis. The available literature is scarce presenting divergent data concerning the clinical outcomes, prognostic factors and variable mutational signature studies. We aim to collect data from the literature and assemble a systematic review. The literature from 2007 until May 2025 was searched using PubMed. Studies bearing data concerning clinical aspects, prognostic outcomes, or molecular characteristics of differentiated high-grade (DHGTC), poorly differentiated (PDTC), and anaplastic thyroid carcinomas (ATC) were retrieved. Original articles in English, ethically conducted on human patients, were selected. From 688 articles, 39 were included. DHGTC has a good 5-year survival rate (5YSR) of 76%, 23.18% metastasis rate, 42.23%, lymph node involvement (LNI), 61.44% extrathyroidal extension (ETE), majority being diagnosed in stage III. PDTC has an intermediate 5YSR of 65.71%, 21.17% distant metastasis, 32.22% LNI, and 55.19% ETE, majority diagnosed in stage III. ATC has a grim 2-year survival rate of 11.15%, 42.15% metastasis, 44.14%, LNI, and 58.51% ETE, majority presented in stage IV-B. Mutational profiling shows that each carcinoma has its unique set of molecular alterations. Most positive prognostic comes for DHGTC, then PDTC, and finally, ATC. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Analyses in Cancer)

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