Search Results (310)

Liquid biopsy, the analysis of tumor-derived material in blood, saliva, and other body fluids, is increasingly explored for the diagnosis, surveillance, and molecular characterization of head and neck squamous cell carcinoma (HNSCC). Its performance, however, is not uniform across the disease, and the reason is fundamentally molecular. human papillomavirus (HPV)-positive oropharyngeal cancers carry viral oncogenes that are absent from the host genome and therefore provide a near ideal, tumor specific circulating marker, whereas HPV-negative tumors are driven by a heterogeneous somatic landscape that offers no single universal target. In this narrative review, we adopt a molecular perspective. We first examine the biological origin of circulating tumor DNA and of the other analytes that liquid biopsy can interrogate including circulating tumor HPV DNA, viral transcripts, microRNAs, extracellular vesicles, and methylation signatures. We then consider how analytical platforms, from droplet digital PCR to next generation and ultrasensitive whole-genome sequencing, translate these molecules into measurements. Only afterward do we discuss the clinical questions, organized by clinical objective rather than by individual study: diagnosis and early detection, prognosis and risk stratification, treatment response monitoring, minimal residual disease and surveillance, and biomarker guided de-escalation in HPV-positive disease. Twelve registered clinical trials, involving approximately 1183 patients, are presented as illustrations of these questions. We close on the biological and technical gaps that still separate promising signals from clinical practice, and on the multi analyte and dynamic strategies most likely to bridge them. At present, liquid biopsy should be regarded as a complementary tool rather than as a replacement for established clinicopathological assessment. Full article

Kidney transplant recipients (KTRs) face a significantly elevated risk of persistent high-risk human papillomavirus (HR-HPV) infection and subsequent anal squamous cell carcinoma (ASCC) due to chronic immunosuppressive therapy impairing immunosurveillance. Despite the markedly increased risk of ASCC in this vulnerable cohort, standardized screening protocols and optimal clinical management guidelines are not exhaustive. Chronically compromised immunosurveillance permits prolonged HR-HPV carriage and viral genome integration, driving oncogenesis via the E6 and E7 oncoproteins. While calcineurin inhibitors exert pro-oncogenic effects, transitioning to mTOR inhibitors offers distinct antiproliferative and antiviral advantages. Early detection relies on risk-stratified screening utilizing digital anorectal examination, anal cytology, and high-resolution anoscopy. For managing anal intraepithelial neoplasia, traditional topical agents and minimally invasive ablative procedures are widely used, although high recurrence rates present a major clinical challenge. This review analyzes HPV pathogenesis and clinical management in KTRs, evaluating the impact of immunosuppressive regimens and exploring innovative diagnostic and therapeutic strategies. To address viral persistence without compromising the allograft, integrating novel non-invasive, target-specific nutraceuticals may represent an interesting complementary approach. Ultimately, mitigating post-transplant ASCC requires a multidisciplinary strategy that couples early localized screening with tailored systemic immunosuppression. Full article

Squamous cell carcinoma of the anal canal (SCAC) is a rare malignancy whose incidence has been steadily increasing worldwide. Persistent infection with high-risk human papillomavirus (HPV), particularly HPV16 and HPV18 genotypes, is the main etiological factor and plays a central role in tumor development. While combined chemoradiotherapy remains the standard treatment for localized disease and achieves high rates of tumor control, a considerable proportion of patients experience recurrence or present with advanced disease. For the latter, therapeutic options remain limited. Over the last decade, advances in genomic profiling have significantly expanded our understanding of SCAC biology. Recurrent alterations affecting the PI3K/AKT/mTOR pathway, especially PIK3CA mutations, have emerged as the most common molecular events, particularly in HPV-positive tumors. Additional alterations involve receptor tyrosine kinase signaling, chromatin remodeling genes, DNA damage response pathways, and components of the MAPK cascade. Moreover, HPV-positive and HPV-negative tumors display distinct molecular features with important prognostic implications. Immunotherapy has recently become an important component of treatment for advanced SCAC, although reliable predictive biomarkers are still lacking. This review summarizes the current evidence on the molecular landscape of SCAC, discusses emerging prognostic and predictive biomarkers, and highlights potential opportunities for the development of more personalized therapeutic strategies. Full article

Non-communicable diseases (NCDs), including cancer, cardiovascular, neurodegenerative, autoimmune, and allergic diseases, account for a significant amount of global morbidity and mortality. Chronic viral infections have not been recognized as NCDs, despite the availability of several therapeutic vaccination strategies against oncogenic viruses, such as the hepatitis B virus (HBV) and the human papillomavirus (HPV). Indeed, chronic viral infection leads to the development and progression of malignancies directly linked to the viruses. These considerations support a connection between NCDs, infectious diseases, and therapeutic vaccination. Recent advances in technology have paved the way to the use of vaccines beyond the prevention of infectious diseases, heralding innovative therapeutic and preventative strategies for a variety of chronic NCDs. Here we will review the state of the art of personalized vaccine strategies for NCDs, with an emphasis on the diverse technological platforms used to develop them, including mRNA and DNA vaccines, viral vectors, dendritic cell-based vaccines, nanoparticle delivery systems, and next-generation adjuvants. The review intends to make the case for personalized and antigen-specific vaccination strategies as a compelling option for precision immunotherapy primarily in oncology, where neoantigen-based vaccines are being developed. In addition, we will also review tolerogenic vaccination strategies, vaccination strategies targeting pathological proteins and pathways in neurodegenerative and cardiovascular diseases, and vaccine-based treatment of chronic viral infections. Current evidence about vaccines suggests that several ways are available to induce an immune response or create tolerance to a disease, and possibly altering its course instead of simply controlling the symptoms. However, many challenges are still to be overcome, including disease variability, how to identify appropriate target antigens, the complexity of manufacturing process, long-term safety, and integration with already established treatments. By virtue of the convergence of multiple fields—immunology, genomics, bioinformatics, and new delivery systems—precision vaccinology is gaining momentum. Thus, it is envisaged that personalized vaccines will be an increasingly essential component of future preventive and therapeutic approaches for non-communicable diseases. Full article

Small cell carcinoma of the cervix (SCCC) is a rare yet highly aggressive subtype of cervical cancer (CC), characterized by early invasion, high metastatic potential, frequent recurrence, and extremely poor prognosis, which severely impairs women’s physical and mental health. Currently, high-risk human papillomavirus (hr-HPV, particularly HPV18) infection is recognized as one of the core drivers underlying the initiation and progression of SCCC. Malignant evolution is not triggered by a single infection event but is cooperatively regulated at multiple molecular levels, including HPV genome integration, critical gene mutations, and aberrant activation of multiple signaling pathways. In addition, SCCC exhibits an HPV-independent oncogenic pathway mainly mediated by somatic mutations in tumor protein 53 (TP53) and retinoblastoma 1 (RB1), thus forming a dual pathogenic mechanism. Based on current clinical understanding and molecular mechanisms, this paper reviews the molecular pathogenesis and subtypes of SCCC, reveals the associations between tumor heterogeneity, therapeutic resistance, and metastasis, and proposes potential novel targets for the treatment of SCCC. This study innovatively presents a closed-loop model of two-way empowerment between basic research and clinical application. It emphasizes that basic research should be oriented toward real clinical problems and highlights the reciprocal feedback of clinical practice on basic research, thereby achieving dynamic iteration and collaborative breakthroughs in both fields. Full article

Cervical carcinoma is predominantly driven by high-risk human papillomavirus (HPV) infection, in which functional inactivation of p53 occurs mainly through viral oncoproteins rather than mutations in the TP53 gene. This raises questions concerning the prognostic relevance of TP53 gene status and p53 protein levels in this tumor type. This study aimed to systematically evaluate the prognostic significance of TP53 mutation status, p53 protein abundance, and selected downstream p53-regulated proteins in cervical carcinoma, with particular focus on tumors carrying wild-type TP53. Clinical and proteomic data from 162 cervical carcinoma patients were retrieved from The Cancer Genome Atlas (TCGA). Protein levels (p53, BAX, p21/CDKN1A, and TIGAR) were assessed using reverse-phase protein array (RPPA) data. Survival analyses were performed using Kaplan–Meier estimates with log-rank testing after stratification into quartile-based expression groups. The vast majority of tumors (~93%) harbored wild-type TP53, and the TP53 mutation status showed no association with patient survival. In tumors with wild-type TP53, p53 protein levels did not significantly correlate with overall survival, indicating a limited prognostic value. In contrast, elevated levels of the pro-apoptotic protein BAX showed a clear tendency to be associated with poorer overall and progression-free survival, suggesting BAX as a potential prognostic marker in this specific molecular context. The expression of p21/CDKN1A showed no prognostic relevance, while high TIGAR levels displayed a slight trend toward poorer survival, although without reaching statistical significance. In summary, in HPV-driven cervical carcinoma, neither the TP53 mutation status nor the p53 protein abundance reliably predict patient outcome. Instead, selected downstream effectors of p53 signaling—particularly BAX—may provide more informative prognostic insights in tumors retaining wild-type TP53. These findings highlight the importance of assessing functional outputs of p53 signaling rather than the p53 status alone in this disease context. Full article

Cervical cancer (CC) affects women worldwide, and more than 95% of cases are caused by persistent infection with high-risk human papillomavirus (HR-HPV), such as type 16, which promotes the progression of precancerous lesions to cancer. This study aimed to identify differentially expressed proteins (DEPs) in biopsies from patients with HPV16+ low-grade squamous intraepithelial lesions (LSILs) and from patients with HPV16+ squamous cell carcinoma (SCC) compared with those from HPV-negative normal cervical tissue (NCT HPV−) controls. The samples were analyzed by high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) using a data-independent acquisition (DIA) approach. Data processing and differential protein expression analysis were performed with the DIA-NN software (Data-Independent Acquisition Neural Networks), followed by bioinformatics analyses, including Venn diagrams, pathway enrichment, functional interactome, The Cancer Genome Atlas (TCGA)-SCC data integration, and Western blot detection. In total, 1607 DEPs associated with cell adhesion and extracellular matrix proteins were identified in LSILs, whereas 1516 DEPs associated with catalytic and transport activities were identified in SCC; the proteins overexpressed in LSILs (332) were enriched in processes such as metabolism, immune response activation, and stress and cell death responses. In contrast, proteins overexpressed in SCC (205) were associated with the cell cycle, DNA damage, drug metabolism, proteasome degradation, methylation, and immune response. Interaction analyses highlighted proteins related to early proteins 1,5,6 and 7 (E1, E5, E6, and E7). In terms of the two DEPs, S100 calcium binding protein A10 (S100A10/p11) and thymidine phosphorylase (TYMP) were detected in patients with LSIL, HSIL, and SCC at the protein level, consistent with their higher transcript levels in public datasets. Given the small, exploratory cohort, these findings are hypothesis-generating, and validation in a larger, balanced, independent cohort is required. In conclusion, this study identified DEPs associated with the progression of premalignant lesions to SCC that may represent candidate biomarkers and therapeutic targets warranting further investigation. Full article

Novel blood biomarkers are crucial for HPV-related cancers to overcome the limitations of imaging and biopsies. This review evaluates the diagnostic performance of circulating cell-free DNA (cfDNA) fragmentomic patterns, distinguishing host-genome integrity from specific viral signatures. Following PRISMA guidelines, we searched PubMed, EMBASE, and Web of Science up to February 2026. Methodological quality was assessed via QUADAS-2, and diagnostic performance was synthesized using a random-effects model. From 489 records, six studies (215 patients, 209 controls) met inclusion criteria. Lacking host-derived fragmentomics data, the analysis focused exclusively on the structural size profiles of circulating viral DNA (cfHPV-DNA). Meta-analysis of four cohorts specifically evaluating these viral fragmentation patterns yielded a pooled Diagnostic Odds Ratio (DOR) of 205.73 (95% CI: 44.72–946.38). Specificity was robust (~100%), with high sensitivity (>90%) for macroscopic disease. However, sensitivity decreased in low-tumor-burden cohorts. cfHPV-DNA fragmentation patterns shows promising diagnostic potential for macroscopic HPV-driven malignancies. However, further studies must determine whether fragment sizing truly outperforms binary viral detection and correlates with disease severity. Furthermore, while current assays exploit the analytical simplicity of viral targets, host-derived fragmentomics remains an overlooked compartment that warrants exploration to determine its true clinical value regarding underlying tumor dynamics. Systematic Review Registration: PROSPERO, identifier: CRD420251052768. Full article

Persistent high-risk human papillomavirus (HPV) infection drives cervical cancer, a leading cause of cancer-related mortality among women in low- and middle-income countries; its clinical course is shaped by the cervicovaginal microbiome, in which Lactobacillus-dominated communities are associated with enhanced viral clearance. Despite this, vaginal probiotic interventions often demonstrate limited colonization efficiency, and autochthonous strain libraries from Central Asia remain absent. We applied a tiered functional screening workflow to a collection of 235 vaginal lactic acid bacterial isolates recovered from 400 women undergoing routine gynecological examination in Astana, Kazakhstan. The workflow sequentially filtered isolates on (i) antimicrobial activity against seven urogenital indicator pathogens using the deferred antagonism assay, (ii) surface adhesion by the Brilis erythrocyte assay, and (iii) biofilm-forming capacity by crystal violet retention and laser-capture-microdissection (LCM) microscopy. Species-level identification of the selected candidate was performed by whole-genome shotgun sequencing followed by Kraken2 taxonomic classification. From 235 isolates, three rounds of phenotypic filtering identified four broad-spectrum antimicrobial candidates (127-3, 127-4, 107-2, 107-4) with non-overlapping inhibitory profiles against seven urogenital indicator strains. Adhesion phenotyping segregated candidates into low- and moderate-adhesion groups, with none reaching the high-adhesion threshold. Among all four candidates, only strain 127-4 produced a reproducible biofilm-associated signal (crystal violet retention OD490 = 0.09 ± 0.07 at 24 h; 0.08 ± 0.03 at 48 h), consistent with early surface attachment under static conditions. Whole-genome shotgun sequencing assigned 97.81% of classified reads to Lactiplantibacillus plantarum, supporting preliminary identification of the selected isolate as L. plantarum strain 127-4. Composite ranking confirmed 127-4 as the only isolate combining broad antimicrobial activity (5/7 indicators), moderate adhesion (specific adhesion index, SPA = 2.95), and a detectable biofilm-associated phenotype. We report the first systematic functional screening of autochthonous cervicovaginal lactic acid bacteria from a Central Asian population and identify L. plantarum 127-4 as a probiotic candidate with an integrated trait profile rarely identified through single-criterion screening approaches. Beyond candidate identification, this work establishes a transferable workflow for assembling functionally annotated vaginal Lactobacillus collections from underrepresented populations, providing a foundation for future population-specific probiotic interventions targeting cervicovaginal health. Full article

Human papillomavirus type 53 (HPV53) is one of the most prevalent HPV genotypes in China, frequently detected in cervical intraepithelial neoplasia and cervical cancer, yet remains outside the coverage of all currently available prophylactic vaccines and is relatively understudied. This study performed a comprehensive analysis of HPV53 clinical infection profiles, genomic diversity, and T-cell epitopes to inform therapeutic vaccine development. Clinical analysis of 158 HPV53-positive patients showed that infections were most prevalent in women aged 40–59 years, with persistent infection identified in 13.3% participants and a subset of cases associated with cervical lesions. Genomic analysis of 134 HPV53 isolates identified four lineages (A-D, with lineage D further subdivided into four sublineages, and an overall nucleotide variability of 4.4%. E2 was the most variable protein while E7 was the most conserved. Immunoinformatic prediction identified 176 HLA class I-restricted T-cell epitopes across E6, E7, E1, and E2, from which 20 candidates were selected for experimental validation. Ten demonstrated strong HLA binding affinity in vitro, and murine immunization identified a E6 peptide VYNFAYTDL as an immunodominant epitope. Three validated epitopes exhibited sequence overlap with 12 to 13 of other 13 high-risk HPV genotypes, suggesting their potential as broadly cross-reactive targets. These findings clarify the genomic diversity and immunogenic epitope landscape of HPV53, providing a foundation for the rational design of therapeutic vaccines. Full article

Background/Objectives: Cervical cancer is mainly driven by persistent infection with high-risk human papillomaviruses (HPV), particularly HPV16 and HPV18. Despite advances in cytology, HPV-DNA testing and vaccination, challenges remain in the triage of HPV-positive individuals, prognostic stratification and prediction of treatment response. Non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs and circular RNAs, together with host genetic factors influencing ncRNA expression and emerging lncRNA-encoded peptides, are increasingly recognized as regulators of HPV-associated carcinogenesis. This review summarizes their biological and potential clinical relevance. Methods: A structured literature search was conducted in PubMed and Scopus. Eligible studies included experimental, clinical, observational, genomic and translational investigations on ncRNA dysregulation, circulating or exosomal ncRNAs, treatment-response signatures, host genetic variation and lncRNA-encoded peptides in HPV-associated cervical precancer and cancer. Results: HPV oncoproteins can reshape host ncRNA networks through transcriptional and epigenetic mechanisms. Several miRNAs, lncRNAs and circRNAs are involved in cell-cycle control, apoptosis, senescence, epithelial–mesenchymal transition, immune regulation, DNA repair and treatment resistance. Circulating, exosomal and urinary ncRNA signatures have shown diagnostic or prognostic potential in exploratory cohorts. Specific lncRNAs, including ENSG00000267838/lnc-LENG9-5 and lncRNA-EME1, have been associated with chemoradiotherapy response and radioresistance. The lncRNA-encoded peptide TUBORF represents a novel preclinical therapeutic candidate, while genetic variation may further modulate lncRNA function in HPV-related cervical cancer. Conclusions: ncRNAs are promising candidates for risk stratification, non-invasive diagnosis, treatment-response prediction and therapeutic development in HPV-associated cervical disease. However, evidence remains exploratory, requiring prospective multicentre validation and standardized workflows before clinical implementation. Full article

Background: Cervical cancer is primarily caused by the human papillomavirus (HPV), with persistent infections progressing to low- (LGSIL) and high-grade (HGSIL) lesions. Emerging evidence indicates that the cervicovaginal microbiota influences HPV persistence and disease progression, although the underlying metabolic mechanisms remain unclear. Therefore, we assessed the relationship between the cervicovaginal microbiota and the metabolic milieu in women with cervical dysplasia and HPV infections. Methods: We recruited 36 non-menopausal, non-pregnant women who were classified as negative, LGSIL, or HGSIL based on pathology and HPV results. Cervical swabs were collected for genomic DNA extraction to characterize bacterial communities using 16S rRNA sequencing and to perform HPV genotyping. Cervical lavages were collected for untargeted metabolomic profiling using Gas Chromatography-Mass Spectrometry. Integrative multiomic analysis was performed using the MIMOSA2 pipeline. Results: Although bacterial community structure was not different between groups, women with HGSIL had higher richness and exhibited a higher abundance of Prevotella bivia, Prevotella buccalis, and Lachnospiraceae G-9 oral taxon 924. Lesion-positive samples had shifts in tyramine and putrescine, biogenic amines linked to cancer development. Specifically, Pseudomonas was identified as a potential contributor to tyramine oxidation. Conclusions: Cervical lesions and HPV risk are associated with shifts in the cervicovaginal microbial metabolic milieu, highlighting the role of low-abundant anaerobic bacteria. Despite the small sample size, biogenic amines were associated with anaerobic taxa and microbial dysbiosis. These findings warrant further assessment of microbial-derived metabolites and their potential to promote tumor progression by driving a pro-inflammatory, metabolically altered microenvironment. Full article

Background: Persistent high-risk human papillomavirus (hrHPV) infection causes over 99% of cervical precancers and cancers worldwide, with HPV genotype 16 (HPV16) responsible for 50% of the cases. Latvia ranks among the top EU countries for cervical cancer incidence and mortality. In the general Latvian population, 4.2% of women are hrHPV-infected, mostly with HPV16. However, information on the circulating HPV16 isolates is missing. Objectives: To study the genomic variability of the Latvian HPV16 isolates, compare them with HPV16 in Europe and across the globe, reveal features associated with the severity of cervical disease and uncover eventual sequence changes due to the national HPV vaccination. Methods: DNA was extracted from the formalin-fixed paraffin-embedded cervical tissues of women diagnosed with cervical intraepithelial neoplasia (CIN) stages I-III and squamous cell carcinoma (SCC) grades 1–3, collected between 2012 and 2024. Samples positive for HPV16 were subjected to whole genome sequencing (WGS) on the Illumina platform (n = 16) or Sanger sequencing of the E6/E7 coding region (n = 31). A consensus HPV16 sequence was generated, and single nucleotide polymorphisms (SNPs) and eventual amino acid substitutions (AAS) were analysed. Results: Complete genomes of 16 HPV16 variants were reconstructed, with 13 related to the European sublineage A1 and 3 to the sublineage A2 references. Sequences showed high conservation; still 93 non-redundant variants were identified. The highest variability was observed for the capsid protein L2, and the lowest, for oncoprotein E7. The prevalence of SNPs and AAS in the Latvian HPV16 variants, specifically in capsid protein L1, did not increase with time, showing no effect of HPV vaccination. Associations between HPV16 sequence features and severity of cervical disease were limited to AAS E6:L90V, which was significantly more common in SCC grade 2/3 than in CINII/III cases (p = 0.015). Conclusions: Highly conserved HPV16 genomes circulating in Latvia harbour a series of unique as well as common nonsynonymous SNPs with respective AAS, with one, AAS E6:L90V, associating with disease severity. No HPV vaccine escape variants were detected. Deciphering complete genomes of HPV16 from CIN and SCC cases in Latvia informs public authorities performing HPV vaccination and is useful for the management of HPV-associated cervical diseases. Full article

Persistence of human papillomavirus (HPV) infection leading to cervical carcinogenesis can be attributed to the action of high-risk HPVs, but there are still some unclear factors involved in the mechanisms of either viral clearance or persistence. Although many infections may be self-limiting and cleared successfully by the immune response of the infected individuals, other infections result in persistent HPV infection. Recent studies indicate that microbiota in the gut and cervicovaginal tract modulate host immune status, mucosal inflammation, and epithelial barrier integrity. All these factors determine susceptibility to persistent infection. Inflammation, overproduction of reactive oxygen species (ROS), genomic instability, and impaired antiviral transcription pathways are associated with dysbiosis. In parallel, redox imbalance contributes to mitochondrial dysfunction, impairing mitochondrial antiviral signaling (MAVS)-dependent interferon responses and attenuating induction of interferon-stimulated genes. Additionally, extracellular vesicles (EVs) further promote immune evasion, metabolic programming, and epigenetic regulation by facilitating the intercellular exchange of viral constituents, microRNAs, and signaling molecules. Through this interconnected network of mechanisms, microbial dysbiosis, mitochondrial disruption, and EV signaling collectively shape a niche conducive to persistence. Unlike previous reviews that primarily examine microbiome alterations, oxidative stress (OS), mitochondrial dysfunction, extracellular vesicles, or immune responses as separate processes, this review integrates clinical and omics findings into a systems-based conceptual framework of HPV persistence. By emphasizing the potential interactions among these interconnected biological systems, we aim to identify points of biological convergence, generate mechanistic hypotheses, and highlight opportunities for future biomarker development and therapeutic intervention. Full article

Cervical cancer (CC) is an alarming global health problem, with predominantly higher incidence, lethal progression, and mortality among women of African ancestry (AA) than women of European ancestry (EA). Although persistent high-risk human papillomavirus (HPV) integration and infection are the key etiological factors, currently available evidence implicates epigenetic reprogramming as a prime contributor to ancestry-associated differences in CC pathogenesis. To address these disparities, we performed genome-wide DNA methylation profiling of HPV-positive cervical intraepithelial neoplasia (CIN) lesions from AA (n = 15) and EA (n = 15) women. Differential methylation analysis identified a distinct epigenomic landscape in AA-CIN lesions, with widespread hypermethylation and hypomethylation at promoter-associated and regulatory CpG sites. Pathway enrichment analyses highlighted dysregulation of ECM-receptor interaction, focal adhesion, PI3K-Akt, MAPK, Ras, Rap1, and RUNX-dependent transcriptional networks. Comparative analysis across CIN grades (CIN1–CIN3) revealed progressive epigenetic reprogramming affecting cell cycles, cytoskeletal dynamics, signaling, and metabolic pathways. Among hypermethylated tumor suppressor genes, SH3GL2 and ARHGAP25 showed significantly higher methylation in AA lesions, accompanied by concomitant loss of their protein expression. MBD1, a methylation-binding regulator, was upregulated in AA-CIN lesions, coinciding with global loss of 5-hydroxymethylcytosine (5hmC), suggesting enhanced transcriptional repression. In contrast, EA lesions retained protein expression and 5hmC levels. Collectively, these findings indicate that early, ancestry-specific epigenetic modifications target tumor suppressor pathways and converge on oncogenic signaling, cytoskeletal remodeling, and cell–cell adhesion. Our study provides mechanistic insight into CC health disparities, identifying SH3GL2 and ARHGAP25 hypermethylation as potential biomarkers, and highlighting epigenetic regulation as a contributor to disparate CC progression in AA women. Full article