Clinical Epigenetics最新文献

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A liquid biopsy approach detects HCC and identifies GJA4 as a potential biomarker for HBV-HCC via plasma cfDNA methylome profiling. 液体活检方法检测HCC,并通过血浆cfDNA甲基组分析确定GJA4作为HBV-HCC的潜在生物标志物。
IF 4.8 2区 医学
Clinical Epigenetics Pub Date : 2025-06-11 DOI: 10.1186/s13148-025-01909-w
Jialing Sun, Xinfeng Sun, Weihuang He, Bingding Huang, Wenxing Feng, Zhiyi Han, Ruyun Ruan, Yuanke Pan, Jinxin Zhu, Jing Li, Xin Zhong, Mengqing Ma, Rui Hu, Minling Lv, Qi Huang, Wei Zhang, Mingji Feng, Jinyu Yi, Pin Cui, Xiaozhou Zhou
{"title":"A liquid biopsy approach detects HCC and identifies GJA4 as a potential biomarker for HBV-HCC via plasma cfDNA methylome profiling.","authors":"Jialing Sun, Xinfeng Sun, Weihuang He, Bingding Huang, Wenxing Feng, Zhiyi Han, Ruyun Ruan, Yuanke Pan, Jinxin Zhu, Jing Li, Xin Zhong, Mengqing Ma, Rui Hu, Minling Lv, Qi Huang, Wei Zhang, Mingji Feng, Jinyu Yi, Pin Cui, Xiaozhou Zhou","doi":"10.1186/s13148-025-01909-w","DOIUrl":"10.1186/s13148-025-01909-w","url":null,"abstract":"<p><strong>Background: </strong>Early detection of hepatocellular carcinoma (HCC) can greatly improve the survival rate of patients. Plasma cfDNA methylation has been shown to have the potential to be a non-invasive method for diagnosing HCC. However, the identified HCC plasma cfDNA methylation sites were less sensitive to early HCC diagnosis. Therefore, we aimed to develop a highly sensitive marker panel based on cell-free DNA (cfDNA) methylation for the detection of HCC.</p><p><strong>Methods: </strong>The study included 374 participants, including 102 healthy individuals, 51 HBV patients, 50 cirrhosis patients, and 171 HCC patients (56 at stage 0 or A according to BCLC staging). Two cfDNA methylation sequencing assays (whole genome bisulfite sequencing (WGBS) and targeted bisulfite sequencing (TBS)) were used along with machine learning modeling to detect HBV-related HCC based on differentially methylated regions (DMR) among the four participant groups.</p><p><strong>Results: </strong>TBS analysis achieved an overall sensitivity of 96.67% at a specificity of 93.7% than alpha-fetoprotein (AFP) of 18%-60%, to discriminate all stages of HCC patients from healthy people, and sensitivity of 90.0% at a specificity of 93.75% to discriminate early-stage HCC patients from healthy people. A number of significant DMRs between HCC and non-cancer groups were identified, providing candidate biomarkers for HCC detection. Among these DMRs, one that locates in the promoter region of GJA4, was found to be consistently present in the whole process of HBV-related HCC carcinogenesis. Using data from TCGA, comparison of expression profile of GJA4 between 160 healthy people and 369 HCC patients further supported this scenario.</p><p><strong>Conclusions: </strong>This study provides biomarkers for detecting, staging and early detection of HCC using plasma cfDNA methylome profiling. Additionally, the dynamic alteration of GJA4 promoter methylation may serve as a molecular clue for studying HBV-related HCC carcinogenesis and prognosis.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"98"},"PeriodicalIF":4.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274319","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
EZH1 deficiency promotes ferroptosis resistance by activating NRF2 in sepsis-associated liver injury. EZH1缺乏通过激活NRF2在败血症相关肝损伤中促进铁中毒抵抗。
IF 4.8 2区 医学
Clinical Epigenetics Pub Date : 2025-06-09 DOI: 10.1186/s13148-025-01892-2
Meihua Mei, Ying You, Ningxin Tan, Xiaoshun He, Junqi Huang
{"title":"EZH1 deficiency promotes ferroptosis resistance by activating NRF2 in sepsis-associated liver injury.","authors":"Meihua Mei, Ying You, Ningxin Tan, Xiaoshun He, Junqi Huang","doi":"10.1186/s13148-025-01892-2","DOIUrl":"10.1186/s13148-025-01892-2","url":null,"abstract":"<p><p>Sepsis-associated acute liver injury (SALI) is a major clinical complication of sepsis due to excessive, unfettered inflammation. In recent years, the role of epigenetic regulatory mechanisms in SALI has been gradually emphasized. Here, we investigated the effects of a Histone-lysine N-methyltransferase EZH1 (Enhancer of zeste homolog 1) inhibition on promoting ferroptosis resistance to activate nuclear factor, erythroid derived 2, like 2 (NRF2) in SALI. We found that EZH1 deficiency improved animal survival in lethal sepsis. EZH1 deficiency mice exhibited alleviated SALI with decreased hepatocellular ferroptosis. EZH1 deficiency attenuated the H3K27me3 modification in the Nfe2l2 promoter, lending to the increased expression and nuclear translocation of NRF2. In the in vitro, LPS-induced ferroptosis model, EZH1 inhibitor DS3201 exhibited an anti-ferroptosis effect, which was reversed NRF2 inhibitor ML385. These findings indicate that EZH1 deficiency or inhibition with DS3201 alleviates ferroptosis in the liver by activating the NRF2, and it is suggested that targeting EZH1 may be a new therapeutic strategy in SALI.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"96"},"PeriodicalIF":4.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257500","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
Multi-locus methylation analyses reveal GNAS methylation defects in three patients with the Beckwith-Wiedemann syndrome phenotype and no molecular defects in the 11p15.5 imprinted region. 多位点甲基化分析显示,3例Beckwith-Wiedemann综合征表型患者存在GNAS甲基化缺陷,11p15.5印迹区无分子缺陷。
IF 4.8 2区 医学
Clinical Epigenetics Pub Date : 2025-06-09 DOI: 10.1186/s13148-025-01907-y
Tatsuki Urakawa, Yuri Kanamaru, Naoko Amano, Akira Uchida, Maki Fukami, Masayo Kagami
{"title":"Multi-locus methylation analyses reveal GNAS methylation defects in three patients with the Beckwith-Wiedemann syndrome phenotype and no molecular defects in the 11p15.5 imprinted region.","authors":"Tatsuki Urakawa, Yuri Kanamaru, Naoko Amano, Akira Uchida, Maki Fukami, Masayo Kagami","doi":"10.1186/s13148-025-01907-y","DOIUrl":"10.1186/s13148-025-01907-y","url":null,"abstract":"<p><strong>Background: </strong>Beckwith-Wiedemann syndrome (BWS) is a congenital imprinting disorder (ID) caused by molecular defects in the 11p15.5 imprinted region, such as hypomethylation of the KCNQ1OT1:TSS-differentially methylated region (KCNQ1OT1-DMR) and hypermethylation of the H19/IGF2:IG-DMR, and maternal CDKN1C pathogenic variants, with various clinical characteristics, including overgrowth and macroglossia. Recently, the concept of Beckwith-Wiedemann spectrum (BWSp) and a clinical scoring system for BWS have been proposed, and cases with four or more points are diagnosed with classic BWS, and 20% of cases with BWS have no molecular defects in the 11p15.5 imprinted region. Pseudohypoparathyroidism type 1B (PHP1B, alias inactivating parathyroid hormone (PTH)/PTH-related protein signaling disorder 3) has characteristics of hormone resistance, particularly PTH, caused by methylation defects in DMRs at the GNAS locus (GNAS-DMRs). Some cases with PHP1B show postnatal overgrowth, which overlaps the BWS-phenotype. However, no studies have conducted a multi-locus methylation analysis for the ID-responsible DMRs other than the DMRs in 11p15.5 in cases with the BWS-phenotype and without molecular defects in the 11p15.5 imprinted region.</p><p><strong>Results: </strong>We conducted methylation analysis using pyrosequencing in 77 patients showing the BWS-phenotype without molecular defects in the 11p15.5 imprinted region. Consequently, we identified three patients with methylation defects in the GNAS-DMRs. Patients 1, 2, and 3 had 9, 5, and 4 points in a BWSp score, respectively. All three patients had macroglossia and postnatal overgrowth. Further analyses, methylation-specific multiple ligation-dependent probe amplification for multiple DMRs, array-based methylation analysis, exome sequencing, array comparative genome hybridization analysis, and microsatellite marker analysis showed 9p deletion in Patient 1 and paternal uniparental isodisomy of chromosome 20 in Patient 2 together with multiple methylation defects in DMRs other than the GNAS-DMRs. Patient 3 had methylation defects in only the GNAS-DMRs.</p><p><strong>Conclusion: </strong>Methylation defects in the GNAS-DMRs can cause the BWS-phenotype. For cases with the BWS-phenotype but no molecular defects in the 11p15.5 imprinted region, methylation analysis for the DMRs at the GNAS locus should be considered.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"97"},"PeriodicalIF":4.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257501","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
Mutational landscape and DNA methylation-based classification of squamous cell carcinoma and urothelial carcinoma. 鳞状细胞癌和尿路上皮癌的突变景观和DNA甲基化分类。
IF 4.8 2区 医学
Clinical Epigenetics Pub Date : 2025-06-08 DOI: 10.1186/s13148-025-01902-3
Min Ren, Midie Xu, Chen Chen, Ran Wei, Qianlan Yao, Liqing Jia, Peng Qi, Qifeng Wang, Qianming Bai, Xiaoli Zhu, Sheng Wu, Qinghua Xu, Xiaoyan Zhou
{"title":"Mutational landscape and DNA methylation-based classification of squamous cell carcinoma and urothelial carcinoma.","authors":"Min Ren, Midie Xu, Chen Chen, Ran Wei, Qianlan Yao, Liqing Jia, Peng Qi, Qifeng Wang, Qianming Bai, Xiaoli Zhu, Sheng Wu, Qinghua Xu, Xiaoyan Zhou","doi":"10.1186/s13148-025-01902-3","DOIUrl":"10.1186/s13148-025-01902-3","url":null,"abstract":"<p><strong>Background: </strong>Identification of the tissue of origin is fundamental for cancer treatment. However, squamous cell carcinomas from different sites lack representative histological and immunohistochemical features. This study aimed to identify mutational profiles and further establish a DNA methylation-based classification for squamous cell carcinoma and urothelial carcinoma. Samples of unambiguous squamous cell carcinomas and urothelial carcinomas were collected for targeted next-generation sequencing and mutational landscape analysis. Moreover, using Illumina methylation BeadChip data from public datasets and a local cohort, we developed a DNA methylation-based classifier utilizing the CatBoost algorithm to identify four common types of squamous cell carcinoma (lung, head and neck, esophagus, and cervix) as well as urothelial carcinoma.</p><p><strong>Results: </strong>The DNA mutational profiles of squamous cell carcinomas from different sites overlapped greatly, and there was no significant difference in tumor mutation burden or microsatellite status. On the basis of public datasets and analyses via various machine learning algorithms, a DNA methylation-based classification containing 106 features by the CatBoost algorithm was constructed and reached an accuracy of 98.79% (490/496) in the training set from PanCanAtlas datasets. The predictive accuracies of the methylation classification in the public validation set and local FUSCC validation set 1 with known primary were 86.96% (340/391) and 84.87% (101/119), respectively. The predictive accuracy for the primary samples (89.66%, 78/87) was obviously greater than that for the metastatic samples (71.88%, 23/32). FUSCC validation set 2 included ten complicated cancer of unknown primary (CUP) samples with squamous cell differentiation. When a well-established 90-gene expression assay was compared with the present classification, our methylation-based classification successfully classified two samples with no eligible RNA expression; the results for four sample were consistent with higher methylation prediction scores in three, and those for two samples were inconsistent. The methylation-based classification results of the remaining two samples were more compatible with the results of the clinical evaluation.</p><p><strong>Conclusion: </strong>We successfully established a DNA methylation-based classification for squamous cell carcinomas (lung, head and neck, esophagus, and cervix) and urothelial carcinomas with outstanding diagnostic performance for the first time. This classification has high potential for clinical translation to address the dilemma of identifying the origin of squamous cell carcinoma of unknown primary.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"95"},"PeriodicalIF":4.8,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246776","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
DNA methylation in monozygotic twins discordant for acute lymphoblastic leukemia: a case report and systematic review. 急性淋巴细胞白血病的同卵双胞胎DNA甲基化不一致:一个病例报告和系统回顾。
IF 4.4 2区 医学
Clinical Epigenetics Pub Date : 2025-06-06 DOI: 10.1186/s13148-025-01906-z
Mao-Ling Sun, Yang Li, Rong-Xi Man, Si-Wen Wang, Rong Guo, Ying Yang, Yu-Qing Pan
{"title":"DNA methylation in monozygotic twins discordant for acute lymphoblastic leukemia: a case report and systematic review.","authors":"Mao-Ling Sun, Yang Li, Rong-Xi Man, Si-Wen Wang, Rong Guo, Ying Yang, Yu-Qing Pan","doi":"10.1186/s13148-025-01906-z","DOIUrl":"10.1186/s13148-025-01906-z","url":null,"abstract":"<p><p>Acute lymphoblastic leukemia (ALL) is a prevalent malignant hematologic disease characterized by the abnormal proliferation and accumulation of immature lymphocytes in bone marrow and lymphoid tissues. In our study, Oxford Nanopore Technologies (ONT) sequencing was performed to investigate four types of methylation modifications-6 mA, CHG, CHH, and CpG-in a pair of monozygotic twins, where one twin has ALL and the other is healthy. The results showed the significant global hypomethylation of CpG sites and an increase in 6 mA, CHG, and CHH methylation in the twin diagnosed with ALL. Notably, the hypomethylation of CpG was particularly increased in the open sea, gene body, and 3'UTR regions, while 6 mA and CHG modifications exhibited high methylation levels in the gene body, TSS1500, TSS200, and 3'UTR regions. Additionally, CHH modifications showed high methylation across all genomic regions. Within the differential methylation loci (DML), we identified several genes related to tumorigenesis and progression (such as ZDHHC11, NBPF1, and TPTE). Furthermore, we systemically reviewed the literatures on leukemia and DNA methylation modifications, providing a comprehensive description of their correlation. In summary, these findings indicate that DNA methylation plays a crucial role in the onset and progression of ALL, offering valuable insights for future research into its impact on leukemia development.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"94"},"PeriodicalIF":4.4,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246775","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
Comparison of enzymatic and bisulfite conversion of circulating cell-free tumor DNA for DNA methylation analyses. 用于DNA甲基化分析的循环无细胞肿瘤DNA的酶和亚硫酸盐转化的比较。
IF 4.8 2区 医学
Clinical Epigenetics Pub Date : 2025-06-04 DOI: 10.1186/s13148-025-01901-4
Stine H Kresse, Evy Marie Thorkildsen, Sara Brandt-Winge, Heidi Pharo, Hege Marie Vedeld, Guro E Lind
{"title":"Comparison of enzymatic and bisulfite conversion of circulating cell-free tumor DNA for DNA methylation analyses.","authors":"Stine H Kresse, Evy Marie Thorkildsen, Sara Brandt-Winge, Heidi Pharo, Hege Marie Vedeld, Guro E Lind","doi":"10.1186/s13148-025-01901-4","DOIUrl":"10.1186/s13148-025-01901-4","url":null,"abstract":"<p><strong>Background: </strong>Detection of DNA methylation biomarkers in circulating cell-free DNA (cfDNA) has great clinical potential for cancer management, but there is a high need for method optimization and standardization. Bisulfite conversion of DNA is the gold-standard pre-treatment method for DNA methylation analyses, but causes also DNA fragmentation and loss. Enzymatic conversion of DNA represents a promising alternative due to the more gentle treatment minimizing damage to DNA. The aim of this study was to evaluate and compare enzymatic and bisulfite conversion to identify the best pre-treatment method for detecting DNA methylation biomarkers in cfDNA from plasma using droplet digital PCR (ddPCR).</p><p><strong>Results: </strong>The performance of the NEBNext Enzymatic Methyl-seq Kit (both the full kit intended for sequencing and the sub-component NEBNext Enzymatic Methyl-seq Conversion Module) and the EpiTect Plus DNA Bisulfite Kit was evaluated and compared using normal cfDNA and tumor cfDNA samples from colorectal cancer patients. The cytosine conversion efficiency was 99-100% for both enzymatic and bisulfite conversion. Enzymatic conversion resulted in longer DNA fragments with higher peak fragment sizes compared to bisulfite conversion, but the DNA recovery was considerably lower after enzymatic conversion (34-47%) compared to bisulfite conversion (61-81%). For enzymatic conversion, the full kit gave slightly better DNA recovery than the conversion module. A comparison of five magnetic bead brands, as well as several different magnetic bead-to-sample ratios revealed no major improvements in DNA recovery for the enzymatic conversion. DNA methylation of the biomarker BCAT1 was detected at similar rates in parallel tumor cfDNA samples pre-treated with either enzymatic or bisulfite conversion. However, enzymatic conversion resulted in lower number of positive droplets for both target and control ddPCR assays, in line with the lower DNA recovery after conversion.</p><p><strong>Conclusions: </strong>Based on a thorough evaluation of enzymatic and bisulfite conversion of cfDNA using ddPCR, bisulfite conversion emerges as the best pre-treatment method due to higher DNA recovery after conversion and higher number of positive droplets in the ddPCR reactions.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"93"},"PeriodicalIF":4.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224568","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
High prevalence of constitutional BRCA1 epimutation in patients with early-onset triple-negative breast cancer. 早发性三阴性乳腺癌患者的体质BRCA1突变高患病率
IF 4.8 2区 医学
Clinical Epigenetics Pub Date : 2025-06-03 DOI: 10.1186/s13148-025-01885-1
Mathias Schwartz, Sabrina Ibadioune, Hélène Delhomelle, Solenn Barraud, Sandrine M Caputo, Olfa Trabelsi-Grati, Marie-Charlotte Villy, Anthony Laugé, Roseline Tang, Etienne Rouleau, Emmanuelle Mouret-Fourme, Dominique Stoppa-Lyonnet, Éric Pasmant, Lisa Golmard, Chrystelle Colas, Ivan Bièche
{"title":"High prevalence of constitutional BRCA1 epimutation in patients with early-onset triple-negative breast cancer.","authors":"Mathias Schwartz, Sabrina Ibadioune, Hélène Delhomelle, Solenn Barraud, Sandrine M Caputo, Olfa Trabelsi-Grati, Marie-Charlotte Villy, Anthony Laugé, Roseline Tang, Etienne Rouleau, Emmanuelle Mouret-Fourme, Dominique Stoppa-Lyonnet, Éric Pasmant, Lisa Golmard, Chrystelle Colas, Ivan Bièche","doi":"10.1186/s13148-025-01885-1","DOIUrl":"10.1186/s13148-025-01885-1","url":null,"abstract":"<p><p>Between 5 and 8% of the general population carry a constitutional methylation of the BRCA1 promoter (\"epimutation\"). Several studies have suggested that these BRCA1 epimutations confer an increased risk of breast cancer, in particular triple-negative breast cancer (TNBC), with an earlier onset than in the general population. However, those studies relied on very few patients with early-onset TNBC. Using specific Methylation-Sensitive High-Resolution Melting, we assessed BRCA1 epimutation prevalence in a large cohort of 112 early-onset (≤ 30 years-old) TNBC patients with no genetic cancer-predisposing pathogenic variants (PVs). We compared this cohort to 87 early-onset TNBC patients carrying cancer-predisposing PVs and to 93 late-onset (≥ 70 years-old) TNBC with no cancer-predisposing PVs. We observed a high prevalence of BRCA1 epimutation in blood cells from early-onset TNBC patients with no cancer-predisposing PVs (38/112, 33.9% [95% confidence interval: 25.4-43.6%]) as compared to early-onset patients with cancer-predisposing PVs (1/87, 1.1% [0.1-7.1%], p value < 0.001) and late-onset patients (11/93, 11.8% [6.3-20.6%], p value < 0.001). These differences remained significant when restricting to epimutations with low variant epiallele frequencies (VEF under 1%). Our results highlight the role of constitutional BRCA1 epimutations in early-onset TNBC risk and call for their integration into multifactorial models used to compute personalized breast cancer risk.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"91"},"PeriodicalIF":4.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215058","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
Maternal loss of mouse Nlrp2 alters the transcriptome and DNA methylome in GV oocytes and impairs zygotic genome activation in embryos. 母鼠Nlrp2缺失会改变GV卵母细胞的转录组和DNA甲基化组,并损害胚胎的合子基因组激活。
IF 4.8 2区 医学
Clinical Epigenetics Pub Date : 2025-06-03 DOI: 10.1186/s13148-025-01889-x
Zahra Anvar, Michael D Jochum, Imen Chakchouk, Momal Sharif, Hannah Demond, Alvin K To, Daniel C Kraushaar, Ying-Wooi Wan, Michael C Mari, Simon Andrews, Gavin Kelsey, Ignatia B Van den Veyver
{"title":"Maternal loss of mouse Nlrp2 alters the transcriptome and DNA methylome in GV oocytes and impairs zygotic genome activation in embryos.","authors":"Zahra Anvar, Michael D Jochum, Imen Chakchouk, Momal Sharif, Hannah Demond, Alvin K To, Daniel C Kraushaar, Ying-Wooi Wan, Michael C Mari, Simon Andrews, Gavin Kelsey, Ignatia B Van den Veyver","doi":"10.1186/s13148-025-01889-x","DOIUrl":"10.1186/s13148-025-01889-x","url":null,"abstract":"<p><strong>Background: </strong>NLRP2 is a subcortical maternal complex (SCMC) protein of mammalian oocytes and preimplantation embryos. SCMC proteins are encoded by maternal effect genes and play a pivotal role in the maternal-to-zygotic transition (MZT), early embryogenesis, and epigenetic (re)programming. Maternal inactivation of genes encoding SCMC proteins has been linked to infertility and subfertility in mice and humans, but the underlying molecular mechanisms for the diverse functions of SCMC proteins, and specifically the role of NLRP2, are incompletely understood.</p><p><strong>Results: </strong>We profiled the DNA methylome of pre-ovulatory germinal-vesicle (GV) oocytes from Nlrp2-null, heterozygous (Het), and wild-type (WT) female mice and assessed the transcriptome of GV oocytes and 2-cell embryos from WT and Nlrp2-null females. The absence or reduction of NLRP2 did not alter the distinctive global DNA methylation landscape of GV oocytes, including their unique bimodal methylome patterns and methylation at the germline differentially methylated regions (gDMRs) of imprinted genes. However, altered methylation was observed in a small subset of oocyte-characteristic hyper- and hypomethylated domains and within a minor fraction of genomic regions, particularly in Nlrp2-null oocytes. Transcriptome profiling revealed substantial differences between the Nlrp2-null and WT GV oocytes, including deregulation of many crucial factors involved in oocyte transcriptome modulation and epigenetic reprogramming. Moreover, maternal absence of NLRP2 significantly altered the transcriptome of heterozygous embryos from Nlrp2-null females compared to WT embryos, whereas the transcriptome of heterozygous embryos from Nlrp2-null males was not significantly different from that of WT embryos. Maternal absence of NLRP2 also negatively impacted MZT, as evidenced by the deregulation of a large subset of zygotic genome activation (ZGA)-related genes.</p><p><strong>Conclusions: </strong>This study demonstrates that NLRP2 is essential for shaping the transcriptome of GV oocytes and preimplantation embryos. Maternal loss of Nlrp2 negatively impacts ZGA. Our findings that the DNA methylome of Het and Nlrp2-null oocytes was subtly changed, and that gene-body DNA methylation differences did not correlate with gene expression differences, suggest that posttranscriptional changes in transcript stability, rather than altered transcription itself, are primarily responsible for the changed transcriptome of Nlrp2-null oocytes.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"92"},"PeriodicalIF":4.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215059","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
Impact of DNA methylation on the recurrence risk of stage I non-small cell lung cancer with EGFR mutations. DNA甲基化对伴有EGFR突变的I期非小细胞肺癌复发风险的影响
IF 4.8 2区 医学
Clinical Epigenetics Pub Date : 2025-06-02 DOI: 10.1186/s13148-025-01899-9
Yunyi Li, Zhihui Yang, Fang Wu, Qingchun Liang, James G Herman, Malcolm V Brock, Wenliang Liu, Fenglei Yu, Xue He, Chen Chen
{"title":"Impact of DNA methylation on the recurrence risk of stage I non-small cell lung cancer with EGFR mutations.","authors":"Yunyi Li, Zhihui Yang, Fang Wu, Qingchun Liang, James G Herman, Malcolm V Brock, Wenliang Liu, Fenglei Yu, Xue He, Chen Chen","doi":"10.1186/s13148-025-01899-9","DOIUrl":"10.1186/s13148-025-01899-9","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have demonstrated that patients with stage IB-IIIA non-small cell lung cancer (NSCLC) harboring EGFR mutations (EGFRm) can significantly benefit from adjuvant therapy with EGFR-TKIs. Nevertheless, there remains controversial in clinical practice about the use of EGFR-TKI adjuvant therapy for patients with stage IB EGFRm NSCLC.</p><p><strong>Methods: </strong>This retrospective cohort study was conducted at the Second Xiangya Hospital of Central South University. From January 2011 to December 2020, completely resected stage IA-IB NSCLC (8th TNM staging) patients with sensitive EGFR mutation were included. FFPE tumor and lymph node specimens were collected and subjected to the 8-gene methylation panel using modified MOB-qMSP approach. We employed stepwise regression to select variables and logistic regression to establish the predictive model. Cross-validation and decision curve analysis were performed.</p><p><strong>Results: </strong>A total of 242 patients with IA2-IB EGFRm NSCLC were included in the study. Among these patients, 86 constituted the recurrence (Rec) group, while 156 formed the non-recurrence (Non-Rec) group. Through stepwise logistic regression, seven crucial feature variables were identified, including five-gene methylation variables (CDO1, TAC1, p16, CDH13, and APC) and two clinical variables (tumor invasion and differentiation). The ROC analysis revealed an AUC of 0.873 for the model with these seven variables. Internal cross-validation demonstrated a model accuracy exceeding 77%. The nomogram and decision curve analysis underscored the clinical utility of the model. We calculated the total score for each patient based on the nomogram and divided the patients into high-risk and low-risk groups. The cumulative risk curves for both groups evidenced that the recurrence risk in the high-risk group was significantly higher than in the low-risk group. We further divided the dataset into two cohorts-stage IA2-IA3 patients and stage IB patients. The model maintained a high AUC value (0.879) in stage IA2-A3 patients.</p><p><strong>Conclusions: </strong>Our study demonstrates that the methylation of five genes-CDO1, TAC1, p16, CDH13, and APC-in N2 lymph nodes represents a strong biomarker panel for predicting recurrence in stage IB EGFRm NSCLC after curative resection. This approach also shows exceptional predictive accuracy for postoperative recurrence in stage IA2-IA3 EGFRm NSCLC.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"90"},"PeriodicalIF":4.8,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207842","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
Epigenetic age acceleration mediates the association between low-grade systemic inflammation and cardiovascular diseases: insight from the NHANES 1999-2002. 表观遗传年龄加速介导低级别全身性炎症和心血管疾病之间的关联:来自NHANES 1999-2002的见解
IF 4.8 2区 医学
Clinical Epigenetics Pub Date : 2025-05-31 DOI: 10.1186/s13148-025-01895-z
Xiaolang Chen, Jin Zhong, Yingnan Lv, Lancheng Wei, Huijiao Zhou, Yongmei Yang, Jinfan Chi, Zhen Lee, Huabei Wu, Haiying Zhang
{"title":"Epigenetic age acceleration mediates the association between low-grade systemic inflammation and cardiovascular diseases: insight from the NHANES 1999-2002.","authors":"Xiaolang Chen, Jin Zhong, Yingnan Lv, Lancheng Wei, Huijiao Zhou, Yongmei Yang, Jinfan Chi, Zhen Lee, Huabei Wu, Haiying Zhang","doi":"10.1186/s13148-025-01895-z","DOIUrl":"10.1186/s13148-025-01895-z","url":null,"abstract":"<p><strong>Background: </strong>Currently, with the global aging of the population, inflammation, recognized as a hallmark in age-related diseases, has been studied and linked to cardiovascular diseases (CVD). However, limited evidence on whether inflammation modifies epigenetic aging and affects CVD risk.</p><p><strong>Methods: </strong>This study included 404 CVD patients and 1941 non-CVD individuals from the 1999-2002 National Health and Nutrition Examination Survey cross-sectional data. Low-grade systemic inflammation was assessed using C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and systemic inflammation response index (SIRI). Epigenetic age accelerations (EAAs) were calculated as the residuals between chronological and epigenetic ages: Horvath age acceleration (AgeAccel), AgeAccelHannum, and AgeAccelPheno. Weighted linear and logistic regression analyzed the associations between exposures and outcomes, with mediating effects assessed using the Sobel test.</p><p><strong>Results: </strong>After adjusting confoundings, the log-transformed NLR and SIRI were positively associated with CVD risk, and the odds ratio (OR) ranges from 1.260 to 1.354 (all P < 0.05). Furthermore, the ln-transformed CRP was positively associated with AgeAccelHannum and AgeAccelPheno, and the coefficient (β) ranges from 0.505 to 1.304 (all P < 0.05); the ln-transformed NLR and SIRI were positively associated with all three EAAs, and the β ranges from 0.392 to 2.212 (all P < 0.005). Additionally, 1-unit increase in AgeAccelHannum and AgeAccelPheno was associated with 2.8% (OR: 1.028, 95% CI 1.007-1.049, P = 0.011) and 3.5% (OR: 1.035, 95% CI 1.014-1.056, P = 0.002) increase in CVD risk, respectively. After adjusting confoundings, mediation analysis showed that AgeAccelHannum mediates 10.44% (P = 0.046) of the association between NLR and CVD risk; and AgeAccelPheno mediates 24.03% (P = 0.009) and 18.16% (P = 0.015) of the NLR-CVD and SIRI-CVD risk associations, respectively.</p><p><strong>Conclusion: </strong>Our results demonstrate that EAAs mediate the association between systemic inflammation and CVD risk, highlighting the potential of a multi-target approach to inflammation and epigenetic modifications for personalized management to reduce CVD risk.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"89"},"PeriodicalIF":4.8,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191566","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}
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