Clinical Epigenetics最新文献

{"title":"Clinical significance and prognostic value of SIRT1 genetic variants in sepsis: a multicenter hospital-based case-control study.","authors":"Junbing He, Meiting Yang, Yao Lin, Wanbing Qin, Ruoxuan Yang, Yuting Qin, Lizhen Liu, Mingwei Xu, Yiming Shao, Qinghua Liu","doi":"10.1186/s13148-025-01944-7","DOIUrl":"https://doi.org/10.1186/s13148-025-01944-7","url":null,"abstract":"<p><strong>Background: </strong>SIRT1 exerts pivotal roles in the pathogenesis of sepsis. However, the clinical relevance of SIRT1 genetic variants in the onset and progression of sepsis remains poorly understood. This multicenter hospital-based case-control study, for the first time, explored the potential genetic association of SIRT1 genetic variants with sepsis, as well as their impact on sepsis-associated inflammation. 785 septic patients and 776 controls from Han Chinese population were enrolled from four large Chinese general hospitals.</p><p><strong>Results: </strong>SIRT1 rs12778366 T > C (785 cases, 776 controls) and rs4746720 T > C (765 cases, 774 controls) polymorphisms were successfully genotyped. No significant differences in the genotype/allele frequencies of SIRT1 polymorphisms between sepsis and control groups. The frequencies of rs4746720 TC/CC genotypes were significantly lower in patients with septic shock than those with sepsis subtype (OR = 0.685, 95% CI = 0.508-0.924, P = 0.014), while the TT genotype and T allele were significantly more frequent in mortality group than those in survivor group (P = 0.004 for genotype, P = 0.010 for allele). Kaplan-Meier survival analysis also showed that patients with the sepsis-associated risk TT genotype at the rs4746720 locus had a lower survival rate than those carrying the TC/CC genotype (log-rank = 7.745, P = 0.005). Another polymorphism rs12778366 was significantly related to 28-day mortality of sepsis, and patients with TT genotype exhibited a greater survival rate than TC/CC genotypes (log-rank = 5.536, P = 0.019). The sepsis-associated risk-T allele of rs4746720 was shown to decrease SIRT1 expression and elevate NF-κB p65 phosphorylation, which was associated with higher expression levels of TNF-α, IL-1β, IL-18 and ICAM-1. Upregulation of SIRT1 led to a notable decrease in LPS-stimulated NF-κB activity and downstream pro-inflammatory cytokine expression in HUVECs.</p><p><strong>Conclusions: </strong>The current research has yielded significant clinical evidence indicating that the SIRT1 rs4746720 and rs12778366 polymorphisms serve as functional variants with potential utility as prognostic markers for sepsis progression. This may improve the identification of high-risk sepsis patients, thereby facilitating early interventions and optimized treatment strategies.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"135"},"PeriodicalIF":4.4,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retrotransposon methylation profiles and survival in Black women with high-grade serous ovarian carcinoma.","authors":"Christelle Colin-Leitzinger, Katherine A Lawson-Michod, Courtney E Johnson, Irma M Vlasac, Sean Yoder, Tania Mesa, Dana Roeber, Chad Huff, Michelle A T Hildebrandt, Kristin Haller, Anthony J Alberg, Elisa V Bandera, Melissa Bondy, Michele L Cote, Theresa Hastert, Edward S Peters, Paul D Terry, Andrew B Lawson, Andrew Berchuck, Brooke L Fridley, Jing-Yi Chern, Jennifer A Doherty, Jeffrey R Marks, Joellen M Schildkraut, Brock C Christensen, Lucas A Salas, Lauren C Peres","doi":"10.1186/s13148-025-01942-9","DOIUrl":"https://doi.org/10.1186/s13148-025-01942-9","url":null,"abstract":"<p><strong>Introduction: </strong>Retrotransposons (REs) constitute nearly half of the genome and include long terminal repeat (LTR) elements, Long INterspersed Elements (LINE), and Short INterspersed Elements (SINE). REs are typically silenced in somatic tissues via DNA methylation but can be reactivated through DNA hypomethylation, potentially impacting gene regulation. Here, we investigate genome-scale profiles of RE methylation in high-grade serous ovarian carcinoma (HGSOC) and associations with survival among Black women.</p><p><strong>Methods: </strong>Methylation levels of LTR, LINE-1, and Alu (type of SINE) in 200 HGSOC tumors were predicted using a random forest approach and clustered using multiple consensus algorithms. Associations between RE methylation clusters and survival were evaluated using Cox proportional hazard regression, adjusting for age, stage, and debulking status. We performed sensitivity analyses restricted to women with late-stage disease and with adjustment for BRCA1/BRCA2 mutations.</p><p><strong>Results: </strong>Two RE methylation clusters were identified. Cluster 1 exhibited a more hypomethylated RE profile (\"Active\"), while Cluster 2 was more hypermethylated (\"Repressed\"). No statistically significant differences in patient or clinical characteristics were observed between clusters. Compared to the Active Cluster, the Repressed Cluster was associated with an increased risk of mortality (HR = 2.41; 95% CI 1.04-5.59) and had a lower proportion of T cells. This association was consistent in sensitivity analyses.</p><p><strong>Conclusion: </strong>A more hypermethylated RE profile was linked to worse survival among Black women with HGSOC, highlighting the potential of RE methylation as a prognostic biomarker. Further research is needed to understand the underlying biological mechanisms and their implications in ovarian cancer biology and treatment.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"134"},"PeriodicalIF":4.4,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nutritional associations with decelerated epigenetic aging: vegan diet in a Dutch population.","authors":"Georges E Janssens, Jenny van Dongen, Lannie Ligthart, Eco J C de Geus, Gajja S Salomons","doi":"10.1186/s13148-025-01934-9","DOIUrl":"https://doi.org/10.1186/s13148-025-01934-9","url":null,"abstract":"<p><strong>Background: </strong>The 2021 Aging Report of the European Union projected significant increases in healthcare costs, with some member states expecting up to a 60% rise over the next 50 years, primarily due to an aging population and related diseases. Interventions targeting aging have been proposed to reduce this burden by extending healthspan. Recent evidence suggests that vegan diets may slow the aging process.</p><p><strong>Results: </strong>Using data from the Netherlands Twin Register (n = 22,124), dietary habits of meat eaters (n = 21,614), pescetarians (n = 294), vegetarians (n = 194), and vegans (n = 22) were examined, which were collected in a 2014-2016 survey period. Health parameters such as BMI, waist circumference, and insulin sensitivity showed improved health with more plant-based diets, though results were not adjusted for confounders. Epigenetic age was assessed using the Hannum, Horvath, PhenoAge, GrimAge, and Dunedin Pace of Aging clocks for 3049 participants with DNA methylation (DNAme) data from a 2004-2011 sample collection period and were compared to calendar age from the time of blood draw. Although discordant twin pairs with and without vegan diets (n = 3) were too few for statistical significance, their results suggested a potential benefit of veganism. In the subpopulation with complete data on DNA methylation, dietary habits, and covariates (n = 1198), veganism was significantly associated with lower epigenetic aging scores on the Hannum and Horvath clocks, even after adjusting for confounders (age, sex, smoking, education, physical activity, BMI, and alcohol use). Analysis of individual covariates in the model found that higher education, physical activity, being female, and non-smoking were associated with reduced epigenetic age, while higher BMI was linked to increased epigenetic age; however, since these parameters were used with the primary purpose of accounting for confounders, caution should be used in interpreting these results. Finally, dietary analysis showed that abstaining from pork was associated with lower biological ages (Dunedin Pace of Aging), whereas abstaining from poultry was linked to higher biological ages (PhenoAge, Dunedin Pace of Aging).</p><p><strong>Conclusions: </strong>Although with a small sample size and a large time gap between nutritional survey collection and blood collection for participant's epigenetic ages, these findings suggest that dietary choices, particularly plant-based diets, may influence epigenetic aging. The results highlight the potential of veganism to reduce epigenetic age and underscore the importance of further research to clarify the relationship between diet and aging. Larger cohorts and clinical trials would be necessary to gain more certainty on our initial findings.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"133"},"PeriodicalIF":4.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between outdoor artificial light at night, circadian health, and LDL-C in intracranial artery atherosclerotic stenosis.","authors":"Le Yang, Quan Wang, He Zheng, Yiqing Wang, Zhigang Miao, Hao Li, Yi Yang","doi":"10.1186/s13148-025-01938-5","DOIUrl":"10.1186/s13148-025-01938-5","url":null,"abstract":"<p><strong>Background: </strong>Outdoor artificial light at night (ALAN) exposure interferes with sleep-wake cycles, leading to sleep disorders, and disrupts metabolic processes, which are closely interconnected. Disruptions in circadian rhythms caused by ALAN may indirectly contribute to metabolic dysregulation, especially in vulnerable populations such as patients with intracranial artery atherosclerotic stenosis (ICAS). This study aimed to evaluate the relationship between outdoor ALAN exposure and low-density lipoprotein cholesterol (LDL-C) control in ICAS patients, and to investigate the underlying mechanisms.</p><p><strong>Methods: </strong>We investigated the relationship between outdoor ALAN exposure and LDL-C control in ICAS patients, estimating residential ALAN levels using satellite images. Sleep quality was assessed using validated questionnaires, and generalized additive models were applied to examine the association between ALAN and LDL-C control. Mechanistic insights were explored through animal-based untargeted metabolomics and DNA methylation analyses.</p><p><strong>Results: </strong>A total of 1010 ICAS patients were included, of whom 32 were classified as having poor LDL-C control after three months of management. We found a significant association between outdoor ALAN intensity and poorer LDL-C (control odds ratio = 1.02, 95% CI 1.00, 1.05 per 1 nW/cm^-2/sr^-1 increase). Sensitivity analyses verified the stability of this association. Metabolic profiling reveals ALAN may regulate lipid metabolism by affecting ATP-binding cassette (ABC) transporter proteins. Additionally, dim ALAN treatment promoted global hypomethylation in mice, while melatonin treatment partially counteracted these effects without reducing the stress response.</p><p><strong>Conclusion: </strong>Increasing ALAN intensity surrounding residences was associated with poorer LDL-C control in ICAS patients, potentially mediated by circadian rhythm disruptions, global methylation levels, and ABC transporter protein expression. These findings suggest that managing urban outdoor lighting could serve as a potential strategy to reduce the public health burden of cerebrovascular and metabolic diseases.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"132"},"PeriodicalIF":4.4,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation profiling for molecular classification of neuroblastoma.","authors":"Maja Löfgren, Anna Djos, Shiva Rezaei, Medha Suman, Per Kogner, Tommy Martinsson, Susanne Fransson, Helena Carén","doi":"10.1186/s13148-025-01936-7","DOIUrl":"10.1186/s13148-025-01936-7","url":null,"abstract":"<p><p>Neuroblastoma is a heterogeneous disease where patient stratification is critical for prognosis and treatment decisions and where it recently has been suggested that the presence of telomere maintenance mechanisms (TMM) should be considered in risk stratification. We investigated the utility of DNA methylation-based classification for neuroblastoma diagnostics by analysing 303 tumours samples from two cohorts. We show that of the total number of cases, an average of 90% of the samples classified as neuroblastoma, while 66% also achieved confident classification into the three NB subclasses: \"MYCN-type\", \"ALT/TERT TMM positive\" and \"TMM negative\". The tumours classified as MYCN-type showed genomic amplification of MYCN (MNA); however, some MYCN-type cases lacked evident MNA, suggesting that epigenetic states might be influenced by other factors such as activating ALK mutations. Survival analysis indicated similar poor survival probabilities for patients classified as TMM positive or MYCN type, distinct from the inferior survival of TMM-negative cases. All cases, with complementary genomic data available, associated with TMM positivity also presented features associated with telomere lengthening mechanisms, including TERT or ATRX alteration. However, some tumours positive for these features, especially TERT rearrangement, classified as MYCN type rather than TMM positive, indicating that MNA and other mechanisms introduce a methylation pattern that supersede or overlap with pattern imposed by TERT. Chromosomal copy number alterations (CNAs) characteristic of methylation subclasses were identified, including 1p deletion and 17q gain in MYCN type and combinations of 11q loss, 3p loss, 7q gain, and 17q gain in TMM-positive cases, highlighting the potential of the methylation arrays to replace SNP arrays for prognostic genomic assessments. Our study demonstrates that DNA methylation-based classification stratifies neuroblastoma into clinically relevant subgroups, aiding diagnostic and prognostic decisions, although discrepancy between genomic features and methylation classification does occur. The interplay between genomic alterations and methylation patterns could give clues into the discrepancy and underscores the complexity of neuroblastoma biology and the need for further research and validation of clinical outcomes of the patients in the respective subclasses.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"131"},"PeriodicalIF":4.4,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LINE-1 Methylation sustains telomere length in pregnant women: effects on pregnancy failure.","authors":"Donato Gemmati, Fabio Scarpellini, Francesca Salvatori, Elisabetta D'Aversa, Roberto Marci, Roberta Capucci, Bianca Antonica, Miriana Grisafi, Elisa Turato, Joanne Vanessa Vargas, Paola Secchiero, Giorgio Zauli, Ajay V Singh, Veronica Tisato","doi":"10.1186/s13148-025-01937-6","DOIUrl":"10.1186/s13148-025-01937-6","url":null,"abstract":"<p><strong>Background: </strong>Pregnancy loss is one of the most common adverse events during the first weeks of gestation, and the incidence increases with maternal age and in presence of selected risk factors. Nonetheless, no risk factors have been identified in most cases, considering these cases unexplained. Fertility rate decreases as maternal age increases and epigenetic age-dependent conditions may favor miscarriage. DNA methylation and telomere length are informative of aging and cell senescence, and their assessment has been evaluated as predictors of successful pregnancy.</p><p><strong>Results: </strong>Telomere length (TL; T/S) and LINE-1 methylation (LINE-1; %) have been assessed in a cohort of 242 pregnant women by comparing spontaneous early miscarriage (EPL, n = 129) with voluntary interruption (VPI, n = 113). Telomere size and LINE-1 methylation rate drastically decreased as the age of women increased (P < 0.000001) with EPL group having lower values (T/S: 322.6 ± 142.0 versus 455.0 ± 290.6; P < 0.000001 and LINE-1 %: 81.66 ± 4.2 versus 86.01 ± 3.7; P < 0.000001) also characterized by stronger age-dependent lowering compared to VPI (P = 0.00035 and P < 0.000001, respectively). A global improvement in TL was observed as LINE-1 methylation rate increased, and it was more evident in EPL than in VPI (P < 0.000001). Focusing on the area below the 25th percentile of TL and LINE-1 % distribution, an overrepresentation of EPL cases was observed (P < 0.000001). On the contrary, VPI controls were dramatically overrepresented (P < 0.000001) in the area above the respective 75th percentiles. The mutual comparison of the number of EPL and VPI in these two extreme areas (EPL/VPI_(<25th) = 3.12 versus EPL/VPI_(>75th) = 0.32) yielded a significant risk of early pregnancy failure when women carried both risk conditions, low TL and LINE-1 methylation (OR = 9.70, 3.94-23.72; P < 0.0001). The intracase analyses ascribed to recurrent EPL cases even higher risks (OR = 10.5, 3.6-29.5; P < 0.0001) and a risk dosage effect stratification recognized to low methylation highest odds than that of short telomeres (OR = 4.44, 2.45-8.03; P < 0.0001 and OR = 2.26, 1.26-4.04; P = 0.005, respectively).</p><p><strong>Conclusions: </strong>Overall, this suggests a combined effect of short telomeres and low methylation in phenotype worsening and a significant role of methylation in sustaining telomere size. These data support the hypothesis that different levels of DNA methylation may capture different biological mechanisms underlying telomere dynamics and dysfunctions and chromatin organization. Therefore, the concomitant assessment of telomere, methylation and their mutual interactions may be a novel strategy to translate the classical informative biomarkers of aging in the field of human reproduction.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"130"},"PeriodicalIF":4.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting PRMT1-mediated methylation of TAF15 to protect against myocardial infarction by inhibiting ferroptosis via the GPX4/NRF2 pathway.","authors":"Guanshen Huang, Liwei He, Bishan Liang, Mingjian Gao, Jianming Huang, Hao Xia, Xinyu Li, Hai Li, Yunjun Ruan","doi":"10.1186/s13148-025-01935-8","DOIUrl":"10.1186/s13148-025-01935-8","url":null,"abstract":"<p><strong>Background: </strong>Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. Ferroptosis, an iron-dependent form of regulated cell death, plays a crucial role in AMI progression. However, the molecular mechanisms regulating ferroptosis in AMI remain poorly understood. This study aims to investigate the role and potential regulatory mechanism of TAF15 in AMI.</p><p><strong>Methods: </strong>Bioinformatics analysis of gene expression datasets was conducted to identify differentially expressed genes in AMI samples. TAF15 expression was evaluated in clinical AMI patient blood samples, ischemia/reperfusion (I/R)-treated HL-1 cardiomyocytes, and myocardial tissues from the AMI mouse model using qRT-PCR and Western blot analyses. Gain- and loss-of-function experiments were performed to assess the effects of TAF15 and PRMT1 on myocardial injury, oxidative stress, and ferroptosis markers (Fe²⁺, MDA, GSH, GPX4, ROS) using electrocardiography, histopathology, CCK-8, EdU, TUNEL, ELISA, flow cytometry, qRT-PCR, and Western blot assays. Mechanistic studies, including luciferase reporter assays, chromatin immunoprecipitation (ChIP-qPCR), and bisulfite sequencing, were conducted to examine PRMT1-mediated TAF15 methylation and its regulatory effects.</p><p><strong>Results: </strong>TAF15 was significantly downregulated in AMI, as observed in patient samples and experimental models. Functionally, TAF15 overexpression significantly improved myocardial function by inhibiting ferroptosis. Notably, TAF15 overexpression restored GPX4 and NRF2 expression, reduced Fe²⁺ accumulation and lipid peroxidation (MDA levels), and increased GSH levels in both HL-1 cardiomyocytes and AMI mouse model. Mechanistic investigations revealed that TAF15 interacted with NRF2, enhancing TAF15 transcription and subsequently activating the GPX4/NRF2 axis, which protects against ferroptosis-induced cardiomyocyte death. Additionally, PRMT1 negatively regulated TAF15 via hypermethylation. PRMT1 knockdown significantly upregulated TAF15 expression, leading to reduced ferroptosis and improved cardiac function.</p><p><strong>Conclusions: </strong>This study establishes TAF15 as a novel regulator of ferroptosis in AMI, activating the GPX4/NRF2 pathway to mitigate oxidative stress and myocardial injury. Furthermore, PRMT1-mediated TAF15 hypermethylation promotes ferroptosis, thereby exacerbating myocardial damage. These findings suggest that targeting the PRMT1/TAF15/GPX4-NRF2 axis represents a promising therapeutic strategy for AMI treatment by inhibiting ferroptotic cell death and improving cardiac function.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"129"},"PeriodicalIF":4.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12285139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144689007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monitoring breast cancer progression through circulating methylated GCM2 and TMEM240 detection.","authors":"Chin-Sheng Hung, Hsieh-Tsung Shen, Pei-Yu Wang, Chih-Ming Su, Wei-Wen Hsu, Kuan-Yu Chien, Cai-Sia Han, Li-Min Liao, Ruo-Kai Lin","doi":"10.1186/s13148-025-01939-4","DOIUrl":"10.1186/s13148-025-01939-4","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths in women worldwide. Approximately 20-30% of women diagnosed with early-stage breast cancer eventually develop metastatic disease. Current biomarkers, such as CA15-3 and CEA, detect metastasis in only 60-80% of cases, underscoring the need for improved diagnostic tools. This study investigates the potential of circulating methylated GCM2 and TMEM240 as biomarkers for noninvasive monitoring of breast cancer progression.</p><p><strong>Methods: </strong>In a prospective study conducted in Taiwan, 396 patients were enrolled, alongside a retrospective study of 134 plasma samples from Western populations. cfDNA was extracted, subjected to sodium bisulfite conversion, and the methylation levels of GCM2 and TMEM240 were measured using QMSP. Monte Carlo analysis assigned 70% of the dataset to a training set and 30% to a validation set, repeated 1000 times. Performance metrics such as sensitivity, specificity, and accuracy were averaged to ensure robustness, supporting the use of combined GCM2 and TMEM240 for monitoring treatment response and tumor burden.</p><p><strong>Results: </strong>The training set, consisting of 166 breast cancer patients (13.3% with recurrence or metastasis), was utilized to establish the biomarker detection cutoff. Validation in a separate cohort of 325 patients (20% with recurrence or metastasis) demonstrated superior performance compared to CA15-3 and CEA, achieving 95.1% accuracy, 89.4% sensitivity, 96.5% specificity, 86.8% positive predictive value (PPV), and 97.3% negative predictive value (NPV). Monte Carlo analysis of the training data revealed an average sensitivity of 95.7%, specificity of 90.3%, and accuracy of 91.5%, while validation data achieved 92.8% sensitivity, 89.5% specificity, and 90.3% accuracy across 1000 replicates. Positive cases were significantly associated with late-stage disease (P < 0.001), larger tumors (P = 0.002), distant metastasis (P < 0.001), and disease progression (P < 0.001). For monitoring treatment response and tumor burden, decreased methylation levels were observed in patients responding well to treatment, whereas increased levels were noted in cases of cancer progression or prior to metastasis.</p><p><strong>Conclusions: </strong>Overall, detecting methylated GCM2 and TMEM240 in plasma offers a novel, accurate, and noninvasive method for monitoring breast cancer progression.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"128"},"PeriodicalIF":4.8,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12281721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation in normal-appearing tissue associated with prostate cancer recurrence and metastasis.","authors":"Christine Aaserød Pedersen, Thomas Fleischer, Maximilian Wess, Elise Midtbust, Maria K Andersen, Trond Viset, Øystein Størkersen, Morten B Rye, May-Britt Tessem","doi":"10.1186/s13148-025-01932-x","DOIUrl":"10.1186/s13148-025-01932-x","url":null,"abstract":"<p><p>There is a need for more precise biomarkers and understanding on the development of aggressive prostate cancer. In this study, we analyzed DNA methylation in 64 prostate cancer tissue samples, using tissue from radical prostatectomy patients (n = 16) with up to 16 years of clinical follow-up. We used several samples from each patient including both normal and cancer tissue to study DNA methylation patterns in relation to aggressiveness measured by follow-up data of biochemical recurrence and metastasis status as clinical endpoints. We identified differentially methylated CpGs associated with recurrence and metastasis, regardless of whether the tissue was normal, cancer-adjacent normal, or cancer. The identified CpG sites were over-represented in promoter regions and transcription factor binding regions, suggesting their influence on gene expression regulation. They further exhibited low intrapatient heterogeneity both between normal, normal adjacent, and cancer tissue, making them favorable as potential biomarkers for aggressive prostate cancer. However, validation of a subset of these CpGs in an external dataset was unsuccessful.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"127"},"PeriodicalIF":4.8,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12281782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multifaceted regulation of the HOX cluster and its implications in oral cancer.","authors":"Kanaka Sai Ram Padam, Keith D Hunter, Raghu Radhakrishnan","doi":"10.1186/s13148-025-01933-w","DOIUrl":"10.1186/s13148-025-01933-w","url":null,"abstract":"<p><strong>Background: </strong>The hypothesis that aberrant expression of homeobox (HOX) transcription factors contributes to oral cancer progression is gaining prominence. However, the mechanism of regulation involved in the clustered dysregulation of HOX clusters is not clearly known.</p><p><strong>Results: </strong>Our findings revealed that HOXA and HOXB clusters showed significant locus-specific CpG methylation changes compared with the HOXC and HOXD clusters. The constitutively unmethylated regions identified in the HOXA1, HOXA11, HOXB5, HOXB6, HOXB9, HOXC5, HOXC10 and HOXC11 genes may be associated with open chromatin-mediated gene regulation. The methylation of CpG loci within the intron of HOXB9 may serve as a potential marker for distinguishing patients with premalignant and advanced oral tumors. HOXA5 and HOXC9 showed higher transcription factor-mediated interactions with neighboring HOX genes within and across the clusters. Additionally, HOXB9 and HOXC10 were predicted to directly regulate the G2-M checkpoint and hypoxia pathways. HOXA genes can be post-transcriptionally regulated through an antisense-mediated mechanism involving embedded HOX long noncoding RNAs (lncRNAs). Posterior HOX genes were more highly expressed than anterior HOX genes. The HOXC and HOXD cluster gene expression patterns were similar to those of the embedded lncRNAs. HOXA1, HOXC13 and HOXD10 were significantly correlated with the cancer hallmarks driving oral carcinogenesis.</p><p><strong>Conclusion: </strong>The functional consequence of HOX genes dysregulation was driven by diverse DNA and RNA epigenetic mechanisms affecting the transcriptional and post-transcriptional regulation contributing to the oral cancer progression.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"126"},"PeriodicalIF":4.8,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}