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Retraction Note: Hypoxia impairs decitabine-induced expression of HLA-DR in acute myeloid leukaemia cell lines.
IF 4.4 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2026-02-09 DOI: 10.1186/s13148-026-02074-4
Sam Humphries, Sean M Burnard, Courtney D Eggins, Simon Keely, Danielle R Bond, Heather J Lee
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引用次数: 0
Trimethylamine N-oxide and related metabolites may regulate DNA methylation and trigger cardiovascular disease.
IF 4.4 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2026-02-09 DOI: 10.1186/s13148-026-02060-w
Jiantao Ma, Chao-Qiang Lai, Xinmin S Li, Meng Wang, Zeneng Wang, Jie Yao, Xiuqing Guo, Kent D Taylor, Soyoung Lee, Russell P Tracy, Durda Peter, Yongmei Liu, Jerome I Rotter, Stephen S Rich, Matthew Budoff, WHWilson Tang, Joseph A DiDonato, Jennifer A Brody, Rozenn N Lemaitre, Amanda Fretts, Nona Sotoodehnia, Bruce M Psaty, José M Ordovás, David S Siscovick, Stanley L Hazen, Dariush Mozaffarian

Background: Trimethylamine N-oxide (TMAO) and its related metabolites have been linked to cardiovascular disease (CVD), but their impact on DNA methylation remains unclear. Investigating these relationships may clarify the role of epigenetic mechanisms in diseases.

Methods: This study analyzed data from 1,356 adults from the Cardiovascular Health Study (CHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Using stable-isotope dilution liquid chromatography with on-line electrospray ionization tandem mass spectrometry (LC-MS), we quantified TMAO and five related metabolites. DNA methylation levels were measured using Illumina BeadChip arrays. Epigenome-wide association analyses and meta-analyses were conducted across approximately 430,000 CpG sites. To explore the functional significance of the identified CpGs, we performed gene set enrichment analysis and Mendelian randomization (MR) analyses.

Results: We identified 143 metabolite-CpG pairs at FDR < 0.05, including four CpGs for TMAO (P ≤ 4.03e-7), 12 for betaine (P ≤ 1.19e-6), 53 for γ-butyrobetaine (P ≤ 6.11e-6), five for carnitine (P ≤ 5.42e-7), six for choline (P ≤ 2.81e-7), and 63 for crotonobetaine (P ≤ 7.25e-6). CpGs associated with γ-butyrobetaine showed moderate correlation with crotonobetaine-associated CpGs. In total, these metabolite-linked CpGs were mapped to 108 genes. Gene set enrichment analysis revealed 145 significantly enriched gene sets, including nine highly relevant to CVD risk. Furthermore, CpGs were enriched in 80 immunologic signature gene sets (FDR < 0.05). MR analysis identified three CpGs associated with coronary artery disease (CAD), including hypermethylation at cg18705301 (NDUFAF1), which was inversely associated with betaine levels and linked to a lower risk of CAD (P = 1.8e-5).

Conclusion: This study identified specific DNA methylation sites associated with TMAO and related metabolites. These epigenetic changes may contribute to CVD risk through multiple pathways. Future research should validate these findings and explore their clinical implications.

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引用次数: 0
Distinct epigenetic aging in sporadic and hereditary neuroendocrine neoplasms.
IF 4.4 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2026-02-09 DOI: 10.1186/s13148-026-02069-1
Shiri Weinstein, Reut Halperin, Amit Tirosh

Background: Epigenetic clocks assess DNA aging based on DNA methylation. We aimed to study the utility of methylation clocks in understanding the distinct characteristics of sporadic and hereditary neuroendocrine neoplasms (NEN).

Methods: Epigenetic age and acceleration were calculated based on Horvath multi-tissue, Levine, and Hannum clocks, and compared by genetic predisposition and NEN grading (WHO-defined G1, G2 and G3).

Results: Following quality assessment and filtering of the data, 93/96 samples were analyzed. Of them, 41/93, 42/93, and 10/93 were sporadic, multiple endocrine neoplasia 1 (MEN1) and von Hippel-Lindau (VHL)-related NEN, respectively. Forty-eight (48/93) were pancreatic NEN (PanNEN). mDNA age positively correlated with chronological age based on three different clock algorithms, but stronger correlations were found in the hereditary NEN subgroups (Horvath clock, r = 0.65, p < 0.001 for MEN1-relatd NEN, and r = 0.86, p = 0.002 in VHL-related NEN). Epigenetic age acceleration was higher in sporadic NEN compared to hereditary NEN, both based on chronological age-adjusted epigenetic age (Hannum clock, sporadic vs. MEN, p = 0.03; sporadic vs. VHL, p = 0.0002), and based on the difference between epigenetic age and chronological age (Hannum clock, sporadic vs. MEN1, p = 0.009; sporadic vs. VHL, p = 0.0005). Finally, epigenetic age (p = 0.04) and age acceleration (p = 0.03) were higher among adult patients with NEN (G2/3 vs. G1).

Conclusions: Epigenetic age and age acceleration analysis demonstrate distinct patterns in sporadic and hereditary NEN, suggesting lower impact of epigenetic alteration or DNA aging in the pathogenesis of hereditary NEN.

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引用次数: 0
Advances in epigenetic therapy for esophageal cancer.
IF 4.4 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2026-02-08 DOI: 10.1186/s13148-026-02073-5
Cheng Ye, Xinxin Yan, Yang Gao

Esophageal cancer is a highly aggressive malignant tumor of the digestive tract, with significant heterogeneity in its pathogenesis and clinical manifestations. Despite advances in treatment strategies such as surgery, chemotherapy, and radiotherapy, the prognosis of esophageal cancer remains poor. In recent years, increasing evidence has shown that epigenetic regulation plays a critical role in the occurrence and development of esophageal cancer. Epigenetic mechanisms, including DNA methylation, histone modification, and non-coding RNA, can regulate gene expression without changing the DNA sequence and are involved in a variety of biological processes, including cell proliferation, apoptosis, and invasion. Abnormal epigenetic alterations are not only key drivers of tumorigenesis but also promising biomarkers and therapeutic targets. This review focuses on the epigenetic mechanisms involved in esophageal cancer and summarizes the latest progress in epigenetic-based therapeutic strategies, including the development and application of DNA methyltransferase inhibitors, histone deacetylase inhibitors, and drugs targeting non-coding RNAs. Moreover, it discusses the challenges and future prospects of epigenetic therapy in the clinical management of esophageal cancer.

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引用次数: 0
Multi-tissue DNA methylation analysis to identify an appropriate surrogate tissue for a unique neurological tissue specific to spina bifida. 多组织DNA甲基化分析,以确定一个合适的替代组织为独特的神经组织特异性脊柱裂。
IF 4.4 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2026-02-05 DOI: 10.1186/s13148-026-02061-9
Gwen Tindula, Sudipta Kumer Mukherjee, Sheikh Muhammad Ekramullah, D M Arman, Joynul Islam, Subrata Kumar Biswas, Md Nafaur Rahman, Md Ziauddin, Ansar Uddin Ahmed, Hafiza Sultana Suchanda, Benjamin C Warf, David C Christiani, Bernardo Lemos, Liming Liang, Andres Cardenas, Maitreyi Mazumdar

Background: Animal models suggest a role of epigenetic mechanisms, including DNA methylation, in neural tube closure; however, studies characterizing DNA methylation profiles in nervous system tissue from humans with spina bifida are limited. In this study, we assessed DNA methylation profiles in dural tissue of infants with spina bifida, collected at the time of surgical closure of the defect, and examined whether whole blood or buccal swab are appropriate surrogate tissues, as they are more practical to collect in large-scale epidemiological studies. DNA methylation was measured in dural tissue, buccal swab, and whole blood samples collected from 27 unique infants using the Illumina Infinium MethylationEPIC BeadChip array.

Results: Correlation analysis for each CpG site comparing DNA methylation from all participants in dural tissue to DNA methylation in whole blood DNA or buccal swab DNA yielded 1555 statistically significant associations for the whole blood analysis and 920 significant associations for the buccal swab analysis at the Bonferroni threshold of significance. We also performed paired analysis, calculating differences between tissues within each individual and then averaging differences across individuals. After accounting for multiple hypothesis testing using the FDR adjustment, 33% of CpG sites assessed were not significantly differentially methylated between dural tissue and whole blood samples, compared to the 27% of sites not differentially methylated between dural tissue and buccal swab samples.

Conclusions: These results suggest that in the absence of dural tissue, both whole blood and buccal swab samples may be considered as surrogates for dural tissue. The study warrants replication in larger groups to validate findings and may assist researchers restricted to more accessible biospecimens (i.e., blood) to further characterize epigenetic contributors to neural tube defect etiology.

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引用次数: 0
Methylation profile characteristics in the H19/IGF2:IG-DMR revealed by long-read sequencing analysis in patients with Beckwith-Wiedemann syndrome having defects in the OCT4/SOX2 binding site. OCT4/SOX2结合位点存在缺陷的Beckwith-Wiedemann综合征患者的长读测序分析揭示了H19/IGF2:IG-DMR的甲基化谱特征。
IF 4.4 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2026-02-03 DOI: 10.1186/s13148-026-02065-5
Hayate Masubuchi, Tatsuki Urakawa, Rika Kosaki, Riki Nishimura, Yasunori Wada, Sumito Dateki, Hideaki Yagasaki, Reiko Kagawa, Yutaka Nishimura, Hidenobu Soejima, Tsutomu Ogata, Maki Fukami, Masayo Kagami

Background: Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder with characteristic clinical features such as overgrowth and macroglossia. Hypermethylation of the H19/IGF2:IG-differentially methylated region (H19-DMR) is identified in 5% of BWS patients. Although defects in the OCT4/SOX2 binding sites (OBS) on the maternal allele have been reported in patients with hypermethylated H19-DMR, the precise methylation patterns in patients with OBS abnormalities remain elusive. Nanopore long-read sequencing (LRS) obtains sequence reads 10-100 kb long together with single-molecule DNA modifications, such as 5-methylcytosines. Furthermore, LRS can separate reads into haplotypes 1 and 2 based on information from single-nucleotide variants and indels on reads. Here, we conducted LRS to elucidate the abnormal hypermethylation patterns of the H19-DMR in BWS patients with and without OBS abnormalities and evaluate the differences between mothers and their offspring in familial cases with OBS abnormalities.

Results: We included 14 sporadic patients and four familial patients from two families with BWS showing hypermethylation of the H19-DMR. Amplicon sequencing for the H19-DMR detected OBS abnormalities in four (28.6%) sporadic cases (three point mutations, one 21-bp microdeletion overlapping OBS), an OBS point mutation in family A, and a 2.6 kb deletion involving OBS in family B. Subsequently, we conducted targeted LRS and examined methylation indexes for 247 CpGs in the H19-DMR in three sporadic patients with OBS abnormalities, two sporadic patients without OBS abnormalities, and all familial patients with OBS abnormalities. In patients with point mutations and a 21-bp microdeletion affecting a single base in OBS, CpGs in the H19-DMR had obvious hypermethylation in the vicinity of OBS and mild-to-moderate hypermethylation with increased distance from OBS; however, in patients with deletions including OBS, CpGs had moderate hypermethylation in the entire H19-DMR. In families A and B, methylation levels were higher in offspring than in their mothers.

Conclusion: Because 28.6% of sporadic patients had OBS abnormalities, genetic examination for OBS should be considered in BWS patients with hypermethylated H19-DMR. LRS analysis for the H19-DMR revealed differences in methylation patterns between patients with and without OBS abnormalities and the methylation levels of each CpG between mothers and their offspring in families with OBS abnormalities.

背景:Beckwith-Wiedemann综合征(BWS)是一种印痕障碍,其临床特征为过度生长和大舌。在5%的BWS患者中发现H19/IGF2: ig差异甲基化区(H19- dmr)的超甲基化。尽管在H19-DMR高甲基化患者中已经报道了母体等位基因OCT4/SOX2结合位点(OBS)的缺陷,但OBS异常患者的精确甲基化模式仍然难以捉摸。纳米孔长读测序(LRS)可以获得10-100 kb长的序列,并进行单分子DNA修饰,如5-甲基胞嘧啶。此外,LRS还可以根据reads上的单核苷酸变异和索引信息将reads分成单倍型1和单倍型2。在这里,我们通过LRS来阐明伴有和不伴有OBS异常的BWS患者中H19-DMR的异常高甲基化模式,并评估家族性OBS异常病例中母亲及其后代之间的差异。结果:我们纳入了来自两个BWS家族的14例散发患者和4例家族性患者,显示H19-DMR高甲基化。H19-DMR扩增子测序在4例(28.6%)零星病例中检测到OBS异常(3个点突变,1个21 bp微缺失重叠OBS), A家族OBS点突变,b家族OBS缺失2.6 kb。随后,我们进行了靶向LRS,并检测了3例OBS异常的零星患者、2例无OBS异常的零星患者和所有OBS异常的家族性患者的H19-DMR中247个CpGs的甲基化指数。在点突变和影响OBS单个碱基的21 bp微缺失的患者中,H19-DMR中的CpGs在OBS附近出现明显的高甲基化,并且随着距离OBS的增加出现轻度至中度的高甲基化;然而,在包括OBS在内的缺失患者中,CpGs在整个H19-DMR中出现中度高甲基化。在家庭A和B中,后代的甲基化水平高于母亲。结论:由于28.6%的散发患者存在OBS异常,H19-DMR高甲基化的BWS患者应考虑进行OBS遗传检查。H19-DMR的LRS分析揭示了有OBS异常和没有OBS异常的患者之间甲基化模式的差异,以及OBS异常家庭中母亲及其后代之间每种CpG的甲基化水平的差异。
{"title":"Methylation profile characteristics in the H19/IGF2:IG-DMR revealed by long-read sequencing analysis in patients with Beckwith-Wiedemann syndrome having defects in the OCT4/SOX2 binding site.","authors":"Hayate Masubuchi, Tatsuki Urakawa, Rika Kosaki, Riki Nishimura, Yasunori Wada, Sumito Dateki, Hideaki Yagasaki, Reiko Kagawa, Yutaka Nishimura, Hidenobu Soejima, Tsutomu Ogata, Maki Fukami, Masayo Kagami","doi":"10.1186/s13148-026-02065-5","DOIUrl":"https://doi.org/10.1186/s13148-026-02065-5","url":null,"abstract":"<p><strong>Background: </strong>Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder with characteristic clinical features such as overgrowth and macroglossia. Hypermethylation of the H19/IGF2:IG-differentially methylated region (H19-DMR) is identified in 5% of BWS patients. Although defects in the OCT4/SOX2 binding sites (OBS) on the maternal allele have been reported in patients with hypermethylated H19-DMR, the precise methylation patterns in patients with OBS abnormalities remain elusive. Nanopore long-read sequencing (LRS) obtains sequence reads 10-100 kb long together with single-molecule DNA modifications, such as 5-methylcytosines. Furthermore, LRS can separate reads into haplotypes 1 and 2 based on information from single-nucleotide variants and indels on reads. Here, we conducted LRS to elucidate the abnormal hypermethylation patterns of the H19-DMR in BWS patients with and without OBS abnormalities and evaluate the differences between mothers and their offspring in familial cases with OBS abnormalities.</p><p><strong>Results: </strong>We included 14 sporadic patients and four familial patients from two families with BWS showing hypermethylation of the H19-DMR. Amplicon sequencing for the H19-DMR detected OBS abnormalities in four (28.6%) sporadic cases (three point mutations, one 21-bp microdeletion overlapping OBS), an OBS point mutation in family A, and a 2.6 kb deletion involving OBS in family B. Subsequently, we conducted targeted LRS and examined methylation indexes for 247 CpGs in the H19-DMR in three sporadic patients with OBS abnormalities, two sporadic patients without OBS abnormalities, and all familial patients with OBS abnormalities. In patients with point mutations and a 21-bp microdeletion affecting a single base in OBS, CpGs in the H19-DMR had obvious hypermethylation in the vicinity of OBS and mild-to-moderate hypermethylation with increased distance from OBS; however, in patients with deletions including OBS, CpGs had moderate hypermethylation in the entire H19-DMR. In families A and B, methylation levels were higher in offspring than in their mothers.</p><p><strong>Conclusion: </strong>Because 28.6% of sporadic patients had OBS abnormalities, genetic examination for OBS should be considered in BWS patients with hypermethylated H19-DMR. LRS analysis for the H19-DMR revealed differences in methylation patterns between patients with and without OBS abnormalities and the methylation levels of each CpG between mothers and their offspring in families with OBS abnormalities.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112472","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}
引用次数: 0
Blood DNA methylation-predicted plasma protein levels and colorectal cancer survival. 血液DNA甲基化-预测血浆蛋白水平和结直肠癌生存。
IF 4.4 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2026-02-01 DOI: 10.1186/s13148-026-02059-3
Alicia R Richards, Maria F Gomez, Bianca I Dowling, Esther Jean-Baptiste, Biljana Gigic, Jane C Figueiredo, Christopher I Li, David Shibata, Adetunji T Toriola, Doratha A Byrd, Cornelia M Ulrich, Paul A Stewart, Erin M Siegel, Jacob K Kresovich

Background: Protein EpiScores are a novel class of DNA methylation (DNAm)-based metrics proposed to measure peripheral immune system characteristics. Although Protein EpiScores have been associated with chronic disease risk, their relationship with colorectal cancer (CRC) survival has not been investigated.

Methods: We generated new genome-wide DNAm data on pre-treatment whole blood samples from a case-control sample of 136 newly diagnosed CRC patients nested in the ColoCare Study and calculated 107 Protein EpiScores using the developer's algorithm. Over a median follow-up of 7.3 years (range: 0.3-13.8 years), 35 (26%) patients experienced disease recurrence, and 47 (35%) died. Protein EpiScore associations with disease-free and overall survival were tested using Cox regression models, adjusted for patient and clinical characteristics, and prognostic discrimination was assessed using Harrell's C-index.

Results: In fully-adjusted models, HCII, VEGFA, CCL17, and LGALS3BP Protein EpiScores were associated with worse disease-free survival (HRs between 1.62 and 1.71, all FDR < 0.05). Adding these Protein EpiScores to traditional clinical prognosis risk factors significantly improved disease-free survival prediction (C-index: 0.64 vs 0.70, P-diff= 0.03). The LGALS3BP Protein EpiScore was associated with worse overall survival (HR: 1.80, 95% CI 1.29, 2.51,P = 0.0005, FDR= 0.056), and improved prediction (C-index: 0.70 vs 0.75, P-diff= 0.02). Protein EpiScores for HCII, LGALS3BP, MMP12, and VEGFA showed positive association with both disease-free and overall survival (HRs > 1.5).

Conclusions: Protein EpiScores are significantly associated with CRC survival. These findings highlight biological pathways underlying CRC prognosis and support the utility of Protein EpiScores for modeling survivorship.

背景:蛋白EpiScores是一类基于DNA甲基化(DNAm)的新型指标,用于测量外周免疫系统特征。尽管蛋白EpiScores与慢性疾病风险相关,但其与结直肠癌(CRC)生存率的关系尚未被调查。方法:我们从ColoCare研究中嵌套的136例新诊断的CRC患者的病例对照样本中获得治疗前全血样本的新的全基因组DNAm数据,并使用开发人员的算法计算107个蛋白EpiScores。中位随访7.3年(范围0.3-13.8年),35例(26%)患者出现疾病复发,47例(35%)患者死亡。使用Cox回归模型检验EpiScore蛋白与无病生存和总生存的相关性,根据患者和临床特征进行调整,并使用Harrell’sc指数评估预后歧视。结果:在完全调整的模型中,HCII、VEGFA、CCL17和LGALS3BP蛋白EpiScores与较差的无病生存相关(hr在1.62 ~ 1.71之间,FDR均< 0.05)。在传统临床预后危险因素中加入这些蛋白EpiScores可显著提高无病生存预测(C-index: 0.64 vs 0.70, P-diff= 0.03)。LGALS3BP蛋白EpiScore与较差的总生存(HR: 1.80, 95% CI 1.29, 2.51,P = 0.0005, FDR= 0.056)和改善的预测(c指数:0.70 vs 0.75, P-diff= 0.02)相关。HCII、LGALS3BP、MMP12和VEGFA的蛋白EpiScores与无病生存期和总生存期呈正相关(HRs为1.5)。结论:蛋白EpiScores与结直肠癌存活显著相关。这些发现强调了CRC预后的生物学途径,并支持蛋白EpiScores在模拟生存方面的应用。
{"title":"Blood DNA methylation-predicted plasma protein levels and colorectal cancer survival.","authors":"Alicia R Richards, Maria F Gomez, Bianca I Dowling, Esther Jean-Baptiste, Biljana Gigic, Jane C Figueiredo, Christopher I Li, David Shibata, Adetunji T Toriola, Doratha A Byrd, Cornelia M Ulrich, Paul A Stewart, Erin M Siegel, Jacob K Kresovich","doi":"10.1186/s13148-026-02059-3","DOIUrl":"10.1186/s13148-026-02059-3","url":null,"abstract":"<p><strong>Background: </strong>Protein EpiScores are a novel class of DNA methylation (DNAm)-based metrics proposed to measure peripheral immune system characteristics. Although Protein EpiScores have been associated with chronic disease risk, their relationship with colorectal cancer (CRC) survival has not been investigated.</p><p><strong>Methods: </strong>We generated new genome-wide DNAm data on pre-treatment whole blood samples from a case-control sample of 136 newly diagnosed CRC patients nested in the ColoCare Study and calculated 107 Protein EpiScores using the developer's algorithm. Over a median follow-up of 7.3 years (range: 0.3-13.8 years), 35 (26%) patients experienced disease recurrence, and 47 (35%) died. Protein EpiScore associations with disease-free and overall survival were tested using Cox regression models, adjusted for patient and clinical characteristics, and prognostic discrimination was assessed using Harrell's C-index.</p><p><strong>Results: </strong>In fully-adjusted models, HCII, VEGFA, CCL17, and LGALS3BP Protein EpiScores were associated with worse disease-free survival (HRs between 1.62 and 1.71, all FDR < 0.05). Adding these Protein EpiScores to traditional clinical prognosis risk factors significantly improved disease-free survival prediction (C-index: 0.64 vs 0.70, P-diff= 0.03). The LGALS3BP Protein EpiScore was associated with worse overall survival (HR: 1.80, 95% CI 1.29, 2.51,P = 0.0005, FDR= 0.056), and improved prediction (C-index: 0.70 vs 0.75, P-diff= 0.02). Protein EpiScores for HCII, LGALS3BP, MMP12, and VEGFA showed positive association with both disease-free and overall survival (HRs > 1.5).</p><p><strong>Conclusions: </strong>Protein EpiScores are significantly associated with CRC survival. These findings highlight biological pathways underlying CRC prognosis and support the utility of Protein EpiScores for modeling survivorship.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":"24"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12879400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099945","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}
引用次数: 0
Epigenome-wide association study of leukocyte telomere length and their effects on smoking-induced lung tumorigenesis: insights from the Dongfeng-Tongji cohort study. 白细胞端粒长度的全表观基因组关联研究及其对吸烟诱导肺肿瘤发生的影响:来自东风-同济队列研究的见解。
IF 4.4 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2026-01-30 DOI: 10.1186/s13148-026-02053-9
Xin Guan, Yuhan Zhou, Shiru Hong, Yi Jiang, Yang Xiao, Chenming Wang, Ming Fu, Hui Zhao, Shengli Chen, Ye Fu, Yingchen Zhang, Yansen Bai, Yuxi Wang, Yingqian You, Yichi Zhang, Shanshan Cheng, Huan Guo

Background: Epigenetic factors underlying telomere length (TL) may provide insight into telomeric homeostasis, with direct links to cigarette smoking and lung cancer susceptibility. It is unclear, nevertheless, to what extent effects of TL and its related DNA methylation on the smoking-induced lung tumorigenesis.

Methods: A case-cohort study is performed within the Dongfeng-Tongji (DFTJ) cohort, including a randomly selected subcohort of 1399 subjects and 359 incident lung cancer cases. We use a linear regression model to conduct EWAS of TL, while the associations of TL and candidate CpGs with lung cancer risk are evaluated using weighted Cox proportional hazard regression models. Furthermore, the causal inference test (CIT) and mediation analysis are used to elucidate the causality of TL and its relevant CpGs in the smoking-induced lung tumorigenesis. The methylation-expression associations are assessed in SY panel (n = 144), adjacent normal lung tissues (n = 32) and solid normal tissues in TCGA (n = 375).

Results: We identified 31 CpGs with significant associations with TL at FDR < 0.05, and their annotated genes are mainly enriched in oxidative stress, energy metabolism and immunity regulation pathways. Among the 31 TL-related CpGs, 3 CpGs showed substantial associations with both lung cancer risk and smoking status (all FDR < 0.1), including cg26563141 in RGPD1/RGPD2, cg03964851in MIR1974/KIAA0825, and cg08976633 in ZNF74. The further mediation analyses suggest that these three CpGs could mediate 2.89%~8.83% effect on lung cancer risk induced by smoking (all FDR < 0.1). The further CIT and multiple mediation analysis reveal that the effect of smoking on lung cancer risk is primarily mediated by TL (> 10%) while being mildly mediated via DNA methylation pathway (< 1%). Also, hypermethylation of cg26563141 is related to low expression of RGPD1 and RGPD2 across blood and tissue samples.

Conclusions: Both TL attrition and the three candidate CpGs showed significant mediation effects on lung cancer risk induced by smoking. These findings provide novel insight into the epigenetic control of telomere homeostasis mechanisms and clues for methylation alteration and TL in smoking-induced lung tumorigenesis.

背景:端粒长度(TL)背后的表观遗传因素可能提供端粒动态平衡的见解,与吸烟和肺癌易感性直接相关。然而,目前尚不清楚TL及其相关DNA甲基化在多大程度上影响吸烟诱导的肺肿瘤发生。方法:在东风-同济(DFTJ)队列中进行病例队列研究,随机选择1399名受试者和359例肺癌病例。我们使用线性回归模型对TL进行EWAS,而使用加权Cox比例风险回归模型评估TL和候选CpGs与肺癌风险的相关性。此外,采用因果推理检验(CIT)和中介分析来阐明TL及其相关CpGs在吸烟致肺肿瘤发生中的因果关系。在SY组(n = 144)、邻近正常肺组织(n = 32)和TCGA实体正常组织(n = 375)中评估甲基化表达的相关性。结果:我们发现31个CpGs在FDR为10%时与TL显著相关,并通过DNA甲基化途径轻度介导(结论:TL损耗和3个候选CpGs在吸烟诱导的肺癌风险中均具有显著的介导作用)。这些发现为研究端粒内稳态的表观遗传控制机制提供了新的见解,并为吸烟诱导的肺肿瘤发生中的甲基化改变和TL提供了线索。
{"title":"Epigenome-wide association study of leukocyte telomere length and their effects on smoking-induced lung tumorigenesis: insights from the Dongfeng-Tongji cohort study.","authors":"Xin Guan, Yuhan Zhou, Shiru Hong, Yi Jiang, Yang Xiao, Chenming Wang, Ming Fu, Hui Zhao, Shengli Chen, Ye Fu, Yingchen Zhang, Yansen Bai, Yuxi Wang, Yingqian You, Yichi Zhang, Shanshan Cheng, Huan Guo","doi":"10.1186/s13148-026-02053-9","DOIUrl":"https://doi.org/10.1186/s13148-026-02053-9","url":null,"abstract":"<p><strong>Background: </strong>Epigenetic factors underlying telomere length (TL) may provide insight into telomeric homeostasis, with direct links to cigarette smoking and lung cancer susceptibility. It is unclear, nevertheless, to what extent effects of TL and its related DNA methylation on the smoking-induced lung tumorigenesis.</p><p><strong>Methods: </strong>A case-cohort study is performed within the Dongfeng-Tongji (DFTJ) cohort, including a randomly selected subcohort of 1399 subjects and 359 incident lung cancer cases. We use a linear regression model to conduct EWAS of TL, while the associations of TL and candidate CpGs with lung cancer risk are evaluated using weighted Cox proportional hazard regression models. Furthermore, the causal inference test (CIT) and mediation analysis are used to elucidate the causality of TL and its relevant CpGs in the smoking-induced lung tumorigenesis. The methylation-expression associations are assessed in SY panel (n = 144), adjacent normal lung tissues (n = 32) and solid normal tissues in TCGA (n = 375).</p><p><strong>Results: </strong>We identified 31 CpGs with significant associations with TL at FDR < 0.05, and their annotated genes are mainly enriched in oxidative stress, energy metabolism and immunity regulation pathways. Among the 31 TL-related CpGs, 3 CpGs showed substantial associations with both lung cancer risk and smoking status (all FDR < 0.1), including cg26563141 in RGPD1/RGPD2, cg03964851in MIR1974/KIAA0825, and cg08976633 in ZNF74. The further mediation analyses suggest that these three CpGs could mediate 2.89%~8.83% effect on lung cancer risk induced by smoking (all FDR < 0.1). The further CIT and multiple mediation analysis reveal that the effect of smoking on lung cancer risk is primarily mediated by TL (> 10%) while being mildly mediated via DNA methylation pathway (< 1%). Also, hypermethylation of cg26563141 is related to low expression of RGPD1 and RGPD2 across blood and tissue samples.</p><p><strong>Conclusions: </strong>Both TL attrition and the three candidate CpGs showed significant mediation effects on lung cancer risk induced by smoking. These findings provide novel insight into the epigenetic control of telomere homeostasis mechanisms and clues for methylation alteration and TL in smoking-induced lung tumorigenesis.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146092339","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}
引用次数: 0
Characterization and clinical implications of CpG island methylator phenotypes of resistant tumors. 耐药肿瘤CpG岛甲基化表型的表征及其临床意义。
IF 4.4 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2026-01-30 DOI: 10.1186/s13148-026-02058-4
Fei Hou, Xu Zhou, Yu-E Huang, Haizhou Liu, Mengqin Yuan, Jiahao Chen, Quan Wang, Wei Jiang

Background: Drug resistance, characterized by high heterogeneity and complex mechanisms, poses a significant challenge in cancer treatment. Stratifying resistant tumors into biologically and clinically meaningful subgroups can improve prognostic evaluation and help guide treatment decisions. However, the DNA methylation-based subtypes of resistant tumors have not yet been comprehensively characterized.

Results: DNA methylation profiles from resistant tumors were retrieved from public database including TCGA and GEO. For each tumor type resistant to a specific treatment drug, consensus clustering based on the most variable methylated probes was conducted to identify the DNA methylation subtypes of resistant tumors. For low-grade glioma (LGG) resistant to Temozolomide, consensus clustering of highly variable CpGs identified two subtypes: cancer resistance CpG island methylator phenotype-positive (CR_CIMP+) and -negative (CR_CIMP-). The CR_CIMP- subtype associates with poorer prognosis, reduced drug response, and more advanced histology, exhibiting higher tumor mutation burden and greater activity in drug resistance-related pathways, such as PI3K/AKT/mTOR signaling. CR_CIMP subtypes with distinct clinical or molecular features were also identified in pancreatic adenocarcinoma and bladder urothelial carcinoma resistant to Gemcitabine, as well as in non-small cell lung cancer resistant to anti-PD1/PD-L1 immunotherapy. Based on predicted drug responses, the study screens candidate drugs for each CR_CIMP subtype. Finally, a random forest model is proposed to predict CR_CIMP subtypes in LGG patients resistant to Temozolomide.

Conclusions: This study uncovers DNA methylation subtypes within resistant tumors, enabling more precise stratification to inform prognosis and therapy selection.

背景:耐药具有高度异质性和复杂的机制,是癌症治疗面临的重大挑战。将耐药肿瘤分层为生物学和临床意义的亚组可以改善预后评估并帮助指导治疗决策。然而,基于DNA甲基化的耐药肿瘤亚型尚未被全面表征。结果:从包括TCGA和GEO在内的公共数据库中检索到耐药肿瘤的DNA甲基化谱。对于每种对特定治疗药物耐药的肿瘤类型,基于最可变的甲基化探针进行共识聚类,以确定耐药肿瘤的DNA甲基化亚型。对于对替莫唑胺耐药的低级别胶质瘤(LGG),高度可变CpGs的共识聚类鉴定出两种亚型:耐药CpG岛甲基化表型阳性(CR_CIMP+)和-阴性(CR_CIMP-)。CR_CIMP-亚型与较差的预后、较低的药物反应和更晚期的组织学相关,表现出更高的肿瘤突变负担和更高的耐药相关通路活性,如PI3K/AKT/mTOR信号通路。在对吉西他滨耐药的胰腺腺癌和膀胱尿路上皮癌,以及抗pd1 /PD-L1免疫治疗耐药的非小细胞肺癌中,也发现了具有不同临床或分子特征的CR_CIMP亚型。根据预测的药物反应,该研究筛选每种CR_CIMP亚型的候选药物。最后,我们提出了一个随机森林模型来预测替莫唑胺耐药LGG患者的CR_CIMP亚型。结论:该研究揭示了耐药肿瘤内的DNA甲基化亚型,使更精确的分层为预后和治疗选择提供信息。
{"title":"Characterization and clinical implications of CpG island methylator phenotypes of resistant tumors.","authors":"Fei Hou, Xu Zhou, Yu-E Huang, Haizhou Liu, Mengqin Yuan, Jiahao Chen, Quan Wang, Wei Jiang","doi":"10.1186/s13148-026-02058-4","DOIUrl":"https://doi.org/10.1186/s13148-026-02058-4","url":null,"abstract":"<p><strong>Background: </strong>Drug resistance, characterized by high heterogeneity and complex mechanisms, poses a significant challenge in cancer treatment. Stratifying resistant tumors into biologically and clinically meaningful subgroups can improve prognostic evaluation and help guide treatment decisions. However, the DNA methylation-based subtypes of resistant tumors have not yet been comprehensively characterized.</p><p><strong>Results: </strong>DNA methylation profiles from resistant tumors were retrieved from public database including TCGA and GEO. For each tumor type resistant to a specific treatment drug, consensus clustering based on the most variable methylated probes was conducted to identify the DNA methylation subtypes of resistant tumors. For low-grade glioma (LGG) resistant to Temozolomide, consensus clustering of highly variable CpGs identified two subtypes: cancer resistance CpG island methylator phenotype-positive (CR_CIMP+) and -negative (CR_CIMP-). The CR_CIMP- subtype associates with poorer prognosis, reduced drug response, and more advanced histology, exhibiting higher tumor mutation burden and greater activity in drug resistance-related pathways, such as PI3K/AKT/mTOR signaling. CR_CIMP subtypes with distinct clinical or molecular features were also identified in pancreatic adenocarcinoma and bladder urothelial carcinoma resistant to Gemcitabine, as well as in non-small cell lung cancer resistant to anti-PD1/PD-L1 immunotherapy. Based on predicted drug responses, the study screens candidate drugs for each CR_CIMP subtype. Finally, a random forest model is proposed to predict CR_CIMP subtypes in LGG patients resistant to Temozolomide.</p><p><strong>Conclusions: </strong>This study uncovers DNA methylation subtypes within resistant tumors, enabling more precise stratification to inform prognosis and therapy selection.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146084543","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}
引用次数: 0
DNA methylation estimates of immune cell abundance have prognostic potential in triple negative breast cancer. 免疫细胞丰度的DNA甲基化估计在三阴性乳腺癌中具有预后潜力。
IF 4.4 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2026-01-27 DOI: 10.1186/s13148-026-02052-w
Sarah Williams, Darren Korbie, Matt Trau, Kelly A Avery-Kiejda, Rodney J Scott, Braydon Meyer, Melissa C Southey, Roger L Milne, Pierre-Antoine Dugué, Susan J Clark, Clare Stirzaker, Ruth Pidsley

Immune infiltration is now recognised as an important prognostic factor in triple negative breast cancer (TNBC). DNA methylation, due to its cell-type specificity, offers a promising approach for quantifying immune cell abundance as a biomarker for risk stratification. Here, we used EpiDISH, a DNA methylation-based cellular deconvolution method, to estimate immune cell proportions from genome-wide methylation data across four independent breast cancer datasets. We show that increased methylation-estimated immune cell percentage in TNBC patients is associated with improved outcomes. This highlights the potential of DNA methylation-based estimates of cell composition for prognosis in TNBC.

免疫浸润现在被认为是三阴性乳腺癌(TNBC)的一个重要预后因素。DNA甲基化由于其细胞类型特异性,为定量免疫细胞丰度作为风险分层的生物标志物提供了一种有希望的方法。在这里,我们使用EpiDISH,一种基于DNA甲基化的细胞反褶积方法,从四个独立的乳腺癌数据集中的全基因组甲基化数据中估计免疫细胞比例。我们发现,TNBC患者中甲基化估计的免疫细胞百分比增加与预后改善有关。这突出了基于DNA甲基化的细胞组成预测TNBC预后的潜力。
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引用次数: 0
期刊
Clinical Epigenetics
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