Clinical Epigenetics最新文献

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.

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.

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.

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.

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.

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.

Background: Histone deacetylases (HDACs) are central epigenetic regulators in non-small cell lung cancer (NSCLC), yet responses to HDAC inhibitors (HDACi) vary markedly between lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC). We asked how the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) rewires lineage-specific transcriptional programs and whether SAHA-aligned modules of genes, rather than individual loci, capture clinically relevant vulnerabilities in each subtype.

Methods: LUAD-like NCI-H1299 (TP53^del, NRAS^Q61K) and LUSC-like NCI-H1703 (TP53^WT, PDGFRA^amp, PIK3CA^E542K) cells were treated with SAHA (10 µM, 24 h) or DMSO. Bulk RNA-seq data were analysed with edgeR (FDR < 0.05, |log₂FC|> 1), followed by GO/Reactome over-representation, Hallmark GSEA, and STRING-based protein-protein interaction mapping. We quantified apoptosis (Annexin V/PI) and motility (scratch assays under mitomycin C). SAHA "feature-sensing" modules were constructed by intersecting SAHA-responsive DEGs with overall-survival-associated genes from GEPIA2 and were scored in 592 LUAD and 551 LUSC tumours. Correlations between HDAC isoforms and module scores were used to define subtype-biased HDAC-module neighbourhoods.

Results: SAHA reprogrammed the transcriptome in both lines (1,098 DEGs in H1299; 1,532 in H1703), enforcing a shared suppression of E2F/G2-M programs but diverging in non-cell-cycle outputs. In LUAD-like H1299, SAHA upregulated morphogenesis/adhesion and KRAS_SIGNALING_DN/EMT-adjacent signatures while dampening interferon/stress pathways, and significantly reduced migration at low dose. In LUSC-like H1703, SAHA triggered a dominant cell-cycle checkpoint shutdown coupled to complement/ECM and inflammatory induction, with stronger apoptosis but only modest short-term migration restraint. Survival-anchored analysis yielded four SAHA feature-sensing modules; the LUAD_RISK module was enriched for cell-cycle/mitotic genes and was attenuated by SAHA, whereas the LUSC_RISK module captured checkpoint, ECM, and stress-response programs preferentially down-regulated in H1703. Both risk modules stratified prognosis and were linked to distinct HDAC-centred neighbourhoods (HDAC7/9-LUAD_RISK and HDAC4/6-LUSC_RISK) in TCGA tumours.

Conclusions: SAHA imposes a common anti-proliferative core but engages distinct lineage-conditioned risk modules in LUAD and LUSC-cell-cycle/migration-linked in LUAD and checkpoint/stress-linked in LUSC. These SAHA feature-sensing modules provide a mechanistic and clinically anchored framework for subtype-tailored HDAC-directed combinations and for future development of HDACi-aligned biomarkers in NSCLC.

Backgound: High-grade B-cell lymphoma with concurrent MYC and BCL2/BCL6 rearrangements (HGBL-DHL) is a highly aggressive disease that is resistant to conventional first-line immunochemotherapeutic regimens. This resistance necessitates the exploration of innovative therapeutic strategies.

Result: In this study, the combination of chidamide and selinexor showed significant synergistic antilymphoma effects in the treatment of HGBL-DHL. The synergistic effects were evidenced by the inhibition of cell proliferation, induction of apoptosis, and perturbation of the cell cycle in cell lines, as assessed by Cell Counting Kit-8, Annexin V/PI staining, and PI staining assays. Furthermore, in a xenograft mouse model of HGBL-DHL, this combination therapy markedly reduced the tumor burden without causing lethal toxicity. At the mechanistic level, the combination of chidamide and selinexor resulted in the synergistic downregulation of survivin and the PI3K/AKT signaling pathway. This dual inhibition was attributed to the interactive effects of the two drugs. The downregulation of key downstream targets of the PI3K/AKT pathway, including c-Myc, MCL1, BCL-XL, cyclin A2, and survivin, was synergistic and aligned with the phenotypic outcomes. Notably, survivin, an anti-apoptotic gene, underwent transcriptional repression by FOXO1 at the level of epigenetic regulation. Chidamide combined with selinexor synergistically down-regulated survivin in both the nucleus, cytoplasm and total protein levels via HDAC/FOXO1/survivin, HDAC3/PI3K/AKT/XPO1/survivin, XPO1/FOXO1/survivin, and XPO1/survivin axes.

Conclusion: Our preclinical data highlighted the potential synergistic efficacy of chidamide and selinexor in targeting HGBL-DHL, providing a rationale for further clinical investigation of this therapeutic combination for the treatment of this refractory disease.

Breast cancer remains a leading cause of morbidity and mortality among women worldwide, with significant heterogeneity in its development and treatment response. Recent advances in understanding the roles of the microbiome and epigenetic regulation have opened new avenues for addressing the complexities of breast cancer progression and therapeutic resistance. This review explores the intricate relationship between the gut and intratumoral microbiomes and epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNAs. Specifically, we examine how microbial metabolites, particularly short-chain fatty acids (SCFAs), regulate gene expression via epigenetic mechanisms, influencing tumor growth, metastasis, and treatment response. The impact of metabolic diseases, including obesity and type 2 diabetes mellitus (T2DM), on breast cancer risk through microbiome-mediated epigenetic changes is also discussed. Furthermore, the review highlights emerging therapeutic strategies that integrate microbiome modulation with epigenetic therapies, including the use of probiotics, dietary interventions, and fecal microbiota transplantation (FMT), as well as DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors. These innovative approaches hold promise for overcoming treatment resistance and improving clinical outcomes in breast cancer patients. Future research should focus on elucidating the molecular pathways through which the microbiome influences epigenetic regulation and developing personalized, microbiome-targeted therapies that enhance the efficacy of existing treatments. By targeting both the genetic and epigenetic drivers of breast cancer, microbiome-based interventions represent a novel frontier in the fight against this challenging disease.

Background: Triple-negative breast cancer (TNBC) is distinguished by high invasiveness and a tendency for recurrence. Recent studies have suggested that E3 ubiquitin ligases play a crucial role in the initiation and progression of various tumors. However, there is still an absence of systematic understanding regarding the specific function and molecular mechanisms of its member gene RNF130 in TNBC.

Methods: This study conducted a comprehensive analysis of large-scale transcriptomic data from databases such as TCGA and GEO. Additionally, single-cell RNA sequencing data from multiple breast cancer samples and their liver metastases were analyzed to evaluate the expression pattern, prognostic significance, and potential regulatory role of RNF130 in the tumor microenvironment. The effects of RNF130 on breast cancer cell proliferation, apoptosis, and chemotherapy sensitivity were explored through in vitro cell experiments and in vivo mouse models. Furthermore, the study screened and evaluated the targeted inhibitory effect of the Traditional Chinese Medicine active component Worenine on RNF130, as well as its combined therapeutic effect with paclitaxel.

Results: The findings indicated that RNF130 was notably overexpressed in breast cancer tissues and associated with unfavorable patient survival outcomes. Single-cell transcriptomic analysis revealed that RNF130 was predominantly enriched in malignant epithelial cell populations and closely associated with tumor immune evasion phenotypes. RNF130 knockdown inhibited proliferation, induced apoptosis, reduced TNF-α pathway activation, and enhanced sensitivity to paclitaxel, whereas RNF130 overexpression exerted the opposite effects. Co-culture experiments further demonstrated that RNF130 depletion promoted M1 macrophage polarization while control cells induced M2-like phenotypes. Additionally, Worenine downregulated RNF130 expression and displayed a synergistic inhibitory effect with paclitaxel.

Conclusion: This study identifies RNF130 as a critical mediator of TNBC progression that regulates tumor growth, apoptosis, immune evasion, and metabolic reprogramming, partly through activation of the TNF-α signaling pathway. Furthermore, Worenine was found to reduce RNF130 expression and enhance the antitumor effect of paclitaxel, suggesting its potential utility in combination therapy for TNBC. These findings provide mechanistic insights into RNF130-driven malignancy and offer a foundation for developing future therapeutic strategies.