Epigenetic Age Acceleration of Stomach Adenocarcinoma Associated With Tumor Stemness Features, Immunoactivation, and Favorable Prognosis.
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SUBMITTER: Hong C
PROVIDER: S-EPMC8012546 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAgeing-associated molecular changes have been assumed to trigger malignant transformations and the epigenetic clock, and the DNA methylation age has been shown to be highly correlated with chronological age. However, the associations between the epigenetic clock and cervical squamous cell carcinoma (CSCC) prognosis, other molecular characteristics, and clinicopathological features have not been systematically investigated. To this end, we computed the DNA methylation (DNAm) age of 252 CSCC patients and 200 normal samples from TCGA and three external cohorts by using the Horvath clock model. We characterized the differences in human papillomavirus (HPV) 16/18 expression, pathway activity, genomic alteration, and chemosensitivity between two DNAm age subgroups. We then used Cox proportional hazards regression and restricted cubic spline (RCS) analysis to assess the prognostic value of epigenetic acceleration.ResultsDNAm age was significantly associated with chronological age, but it was differentiated between tumour and normal tissue (P < 0.001). Two DNAm age groups, i.e. DNAmAge-ACC and DNAmAge-DEC, were identified; the former had high expression of the E6/E7 oncoproteins of HPV16/18 (P < 0.05), an immunoactive phenotype (all FDRs < 0.05 in enrichment analysis), CpG island hypermethylation (P < 0.001), and lower mutation load (P = 0.011), including for TP53 (P = 0.002). When adjusted for chronological age and tumour stage, every 10-year increase in DNAm age was associated with a 12% decrease in fatality (HR 0.88, 95% CI 0.78-0.99, P = 0.03); DNAmAge-ACC had a 41% lower mortality risk and 47% lower progression rate than DNAmAge-DEC and was more likely to benefit from chemotherapy. RCS revealed a positive non-linear association between DNAm age and both mortality and progression risk (both, P < 0.05).ConclusionsDNAm age is an independent predictor of CSCC prognosis. Better prognosis, overexpression of HPV E6/E7 oncoproteins, and higher enrichment of immune signatures were observed in DNAmAge-ACC tumours.
| S-EPMC7011257 | biostudies-literature
Project description:Properly stratifying high-risk individuals with early stage hepatocellular carcinoma (HCC) is essential to identify patients in which the potentially therapies can be offered. To this context, we systematically investigated the prognostic value of epigenetic clock with early stage HCC as well as the association with other molecular characteristics.We computed DNA methylation (DNAm) age of 256 early stage HCC patients and 50 normal samples from TCGA by Horvath clock model. The characteristics of two DNAm age subgroups were differentiated regarding HBV expression, pathway activity, epigenomic, and genomic alteration. Cox regression and restricted cubic spline (RCS) analysis were utilized to evaluate the prognostic value of epigenetic acceleration.DNAm age was significantly associated with chronological age in normal tissue but largely disrupted in tumors (P< .001), and showed significant negative correlation with HBV expression (P< .05). We identified two DNAm age groups (DNAmAge-ACC and DNAmAge-DEC), and the former presented with an immunoactive phenotype (all FDRs<0.05 in enrichment analysis), CpG island hypermethylation (P< .001), and lower mutation burden (P= .018). Every 10-year increase in DNAm age was associated with a 18% decrease in fatality after adjustment for major clinical variables; DNAmAge-ACC had 50% lower mortality risk than DNAmAge-DEC (HR: 0.50, 95% CI: 0.27-0.94, P= .03). RCS revealed the fatality risk significantly decreased as epigenetic age accelerated (P = .04). Conclusions.In summary, we highlighted the prognostic value of epigenetic age acceleration for early stage HCC; better prognosis, relatively lower HBV load, and higher enrichment of immune signatures were tightly associated with epigenetic age accelerated tumors.
| S-EPMC7646381 | biostudies-literature
Project description:The purpose of our study is to identify epigenetic markers that are differently expressed in the stomach adenocarcinoma (STAD) condition. Based on data from The Cancer Genome Atlas (TCGA), we were able to detect an age-related difference in methylation patterns and changes in gene and miRNA expression levels in young (n = 14) and old (n = 70) STAD subjects. Our analysis identified 323 upregulated and 653 downregulated genes in old STAD subjects. We also found 76 miRNAs with age-related expression patterns and 113 differentially methylated genes (DMGs), respectively. Our further analysis revealed that significant upregulated genes (n = 35) were assigned to the cell cycle, while the muscle system process (n = 27) and cell adhesion-related genes (n = 57) were downregulated. In addition, by comparing gene and miRNA expression with methylation change, we identified that three upregulated genes (ELF3, IL1β, and MMP13) known to be involved in inflammatory responses and cell growth were significantly hypomethylated in the promoter region. We further detected target candidates for age-related, downregulated miRNAs (hsa-mir-124-3, hsa-mir-204, and hsa-mir-125b-2) in old STAD subjects. This is the first report of the results from a study exploring age-related epigenetic biomarkers of STAD using high-throughput data and provides evidence for a complex clinicopathological condition expressed by the age-related STAD progression.
| S-EPMC4406278 | biostudies-literature
Project description:Schizophrenia is a serious neuropsychiatric disorder with abnormal age-related neurodevelopmental (or neurodegenerative) trajectories. Although an accelerated aging hypothesis of schizophrenia has been proposed, the quantitative study of the disruption of the physiological trajectory caused by schizophrenia is inconclusive. In this study, we employed 3 "epigenetic clock" methods to quantify the epigenetic age of a large sample size of whole blood (1069 samples from patients with schizophrenia vs 1264 samples from unaffected controls) and brain tissues (500 samples from patients with schizophrenia vs 711 samples from unaffected controls). We observed significant positive correlations between epigenetic age and chronological age in both blood and brain tissues from unaffected controls and patients with schizophrenia, as estimated by 3 methods. Furthermore, we observed that epigenetic age acceleration was significantly delayed in schizophrenia from the whole blood samples (aged 20-90 years) and brain frontal cortex tissues (aged 20-39 years). Intriguingly, the genes regulated by the epigenetic clock also contained schizophrenia-associated genes, displaying differential expression and methylation in patients with schizophrenia and involving in the regulation of cell activation and development. These findings were further supported by the dysregulated leukocyte composition in patients with schizophrenia. Our study presents quantitative evidence for a neurodevelopmental model of schizophrenia from the perspective of a skewed "epigenetic clock." Moreover, landmark changes in an easily accessible biological sample, blood, reveal the value of these epigenetic clock genes as peripheral biomarkers for schizophrenia.
| S-EPMC8084439 | biostudies-literature
Project description:Study questionIs the use of ART, a proxy for infertility, associated with epigenetic age acceleration?Summary answerThe epigenetic age acceleration measured by Dunedin Pace of Aging methylation (DunedinPoAm) differed significantly between non-ART and ART mothers.What is known alreadyAmong mothers who used ART, epigenetic age acceleration may be associated with low oocyte yield and poor ovarian response. However, the difference in epigenetic age acceleration between non-ART and ART mothers (or even fathers) has not been examined.Study design, size, durationThe Norwegian Mother, Father and Child Cohort Study (MoBa) recruited pregnant women and their partners across Norway at around 18 gestational weeks between 1999 and 2008. Approximately 95 000 mothers, 75 000 fathers and 114 000 children were included. Peripheral blood samples were taken from mothers and fathers at ultrasound appointments or from mothers at childbirth, and umbilical cord blood samples were collected from the newborns at birth.Participants/materials, setting, methodsAmong the MoBa participants, we selected 1000 couples who conceived by coitus and 894 couples who conceived by IVF (n = 525) or ICSI (n = 369). We measured their DNA methylation (DNAm) levels using the Illumina MethylationEPIC array and calculated epigenetic age acceleration. A linear mixed model was used to examine the differences in five different epigenetic age accelerations between non-ART and ART parents.Main results and the role of chanceWe found a significant difference in the epigenetic age acceleration calculated by DunedinPoAm between IVF and non-ART mothers (0.021 years, P-value = 2.89E-06) after adjustment for potential confounders. Further, we detected elevated DunedinPoAm in mothers with tubal factor infertility (0.030 years, P-value = 1.34E-05), ovulation factor (0.023 years, P-value = 0.0018) and unexplained infertility (0.023 years, P-value = 1.39E-04) compared with non-ART mothers. No differences in epigenetic age accelerations between non-ART and ICSI fathers were found. DunedinPoAm also showed stronger associations with smoking, education and parity than the other four epigenetic age accelerations.Limitations, reasons for cautionWe were not able to determine the directionality of the causal pathway between the epigenetic age accelerations and infertility. Since parents' peripheral blood samples were collected after conception, we cannot rule out the possibility that the epigenetic profile of ART mothers was influenced by the ART treatment. Hence, the results should be interpreted with caution, and our results might not be generalizable to non-pregnant women.Wider implications of the findingsA plausible biological mechanism behind the reported association is that IVF mothers could be closer to menopause than non-ART mothers. The pace of decline of the ovarian reserve that eventually leads to menopause varies between females yet, in general, accelerates after the age of 30, and some studies show an increased risk of infertility in females with low ovarian reserve.Study funding/competing interest(s)This study was partly funded by the Research Council of Norway (Women's fertility, project no. 320656) and through its Centres of Excellence Funding Scheme (project no. 262700). M.C.M. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement number 947684). The authors declare no conflict of interest.Trial registration numberN/A.
| S-EPMC9433848 | biostudies-literature
Project description:DNA methylation (DNAm) age estimators are widely used to study aging-related conditions. It is not yet known whether DNAm age is associated with the accumulation of stochastic epigenetic mutations (SEMs), which reflect dysfunctions of the epigenetic maintenance system. Here, we defined epigenetic mutation load (EML) as the total number of SEMs per individual. We assessed associations between EML and DNAm age acceleration estimators using biweight midcorrelations in four population-based studies (total n = 6,388). EML was not only positively associated with chronological age (meta r = 0.171), but also with four measures of epigenetic age acceleration: the Horvath pan tissue clock, intrinsic epigenetic age acceleration, the Hannum clock, and the GrimAge clock (meta-analysis correlation ranging from r = 0.109 to 0.179). We further conducted pathway enrichment analyses for each participant's SEMs. The enrichment result demonstrated the stochasticity of epigenetic mutations, meanwhile implicated several pathways: signaling, neurogenesis, neurotransmitter, glucocorticoid, and circadian rhythm pathways may contribute to faster DNAm age acceleration. Finally, investigating genomic-region specific EML, we found that EMLs located within regions of transcriptional repression (TSS1500, TSS200, and 1stExon) were associated with faster age acceleration. Overall, our findings suggest a role for the accumulation of epigenetic mutations in the aging process.
| S-EPMC7585066 | biostudies-literature
Project description:BackgroundCardiovascular health (CVH) has been defined by the American Heart Association (AHA) as the presence of the "Life's Simple 7" ideal lifestyle and clinical factors. CVH is known to predict longevity and freedom from cardiovascular disease, the leading cause of death for women in the United States. DNA methylation markers of aging have been aggregated into a composite epigenetic age score, which is associated with cardiovascular morbidity and mortality. However, it is unknown whether poor CVH is associated with acceleration of aging as measured by DNA methylation markers in epigenetic age.Methods and resultsWe performed a cross-sectional analysis of racially/ethnically diverse post-menopausal women enrolled in the Women's Health Initiative cohort recruited between 1993 and 1998. Epigenetic age acceleration (EAA) was calculated using DNA methylation data on a subset of participants and the published Horvath and Hannum methods for intrinsic and extrinsic EAA. CVH was calculated using the AHA measures of CVH contributing to a 7-point score. We examined the association between CVH score and EAA using linear regression modeling adjusting for self-reported race/ethnicity and education. Among the 2,170 participants analyzed, 50% were white and mean age was 64 (7 SD) years. Higher or more favorable CVH scores were associated with lower extrinsic EAA (~ 6 months younger age per 1 point higher CVH score, p < 0.0001), and lower intrinsic EAA (3 months younger age per 1 point higher CVH score, p < 0.028).ConclusionsThese cross-sectional observations suggest a possible mechanism by which ideal CVH is associated with greater longevity.
| S-EPMC7905851 | biostudies-literature
Project description:Epigenetic age acceleration-the difference between an individual's DNA methylation age and chronological age-is associated with many diseases including cancer. This study aims to evaluate epigenetic age acceleration as a prognostic biomarker for gliomas. DNA methylation data of gliomas patients (516 low-grade and intermediate-grade gliomas and 140 glioblastoma) were obtained from The Cancer Genome Atlas (TCGA) and patient epigenetic ages were computed using Horvath's age prediction model. We used multivariate linear regression to assess the association of epigenetic age acceleration with tumor molecular subtypes, including Codel, Classic-like, G-CIMP-high, G-CIMP-low, Mesenchymal-like and PA-like. Compared with Codel subtype, epigenetic ages in other molecular subtypes show deceleration after controlling age and race. Age deceleration for Classic-like, G-CIMP-high, G-CIMP-low, Mesenchymal-like and PA-like were 15.42 years (CI: 7.98-22.86, p = 5.38E-05), 25.00 years (CI: 20.79-29.22, p = 4.06E-28), 28.56 years (CI: 14.37-42.74, p = 8.75E-05), 45.34 years (CI: 38.80-51.88, p = 2.15E-36), and 53.58 years (CI: 44.90-62.26, p = 4.81E-30), respectively. Then, Cox proportional hazards regression was used to assess the association of epigenetic age acceleration with patient overall survival. Our results show epigenetic age acceleration is positively associated with patient overall survival (per 10-year age acceleration, HR = 0.89; 95%CI: 0.82-0.97; p = 9.04E-03) in multivariate analysis. When stratified by molecular subtypes, epigenetic age acceleration remains positively associated with patient survival after adjusting age and tumor grade. In conclusion, epigenetic age acceleration is significantly associated with molecular subtypes and patient overall survival in gliomas, indication that epigenetic age acceleration has potential as a quantitative prognostic biomarker for gliomas.
| S-EPMC7373289 | biostudies-literature
Project description:DNA methylation age (DNAm age) estimation is a powerful biomarker of human ageing. To date, epigenetic clocks have not been evaluated in age-related macular degeneration (AMD). Here, we perform genome-wide DNA methylation analyses in blood of AMD patients with a documented smoking history (14 AMD, 16 Normal), identifying loci of differential methylation (DML) with a relaxed p-value criterion (p ≤ 10-4). We conduct DNAm age analyses using the Horvath-multi tissue, Hannum and Skin & Blood epigenetic clocks in both blood and retinal pigment epithelium (RPE). We perform Ingenuity Pathway Analysis Causal Network Analysis (IPA CNA) on the topmost significantly differentially methylated CpG probes in blood and RPE. Results show poor performance of epigenetic clocks in RPE. Epigenetic age acceleration (EAA) was not observed in AMD. However, we observe positive EAA in blood of smokers, and in smokers with AMD. DML analysis revealed hypomethylation at cg04953735 within RPTOR (p = 6.51 × 10-5; Δβ = -11.95%). IPA CNA in the RPE also identified RPTOR as the putative master regulator, predicted to be inhibited in AMD. In conclusion, this is the first study evaluating an association of epigenetic ageing in AMD. We posit a role for RPTOR as a common master regulator of methylation changes in the RPE in AMD.
| S-EPMC8705580 | biostudies-literature
Project description:BackgroundStomach adenocarcinoma (STAD), which accounts for approximately 95% of gastric cancer types, is a malignancy cancer with high morbidity and mortality. Tumor angiogenesis plays important roles in the progression and pathogenesis of STAD, in which long noncoding RNAs (lncRNAs) have been verified to be crucial for angiogenesis. Our study sought to construct a prognostic signature of angiogenesis-related lncRNAs (ARLncs) to accurately predict the survival time of STAD.MethodsThe RNA-sequencing dataset and corresponding clinical data of STAD were acquired from The Cancer Genome Atlas (TCGA). ARLnc sets were obtained from the Ensemble genome database and Molecular Signatures Database (MSigDB, Angiogenesis M14493, INTegrin pathway M160). A ARLnc-related prognostic signature was then constructed via univariate Cox and multivariate Cox regression analysis in the training cohort. Survival analysis and Cox regression were performed to assess the performance of the prognostic signature between low- and high-risk groups, which was validated in the validation cohort. Furthermore, a nomogram that combined the clinical pathological characteristics and risk score conducted to predict the overall survival (OS) of STAD. In addition, ARLnc-mRNA coexpression pairs were constructed with Pearson's correlation analysis and visualized to infer the functional annotation of the ARLncs by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The expression of four ARLncs in STAD and their correlation with the angiogenesis markers, CD34 and CD105, were also validated by RT-qPCR in a clinical cohort.ResultsA prognostic prediction signature including four ARLncs (PVT1, LINC01315, AC245041.1, and AC037198.1) was identified and constructed. The OS of patients in the high-risk group was significantly lower than that of patients in the low-risk group (p < 0.001). The values of the time-dependent area under the curve (AUC) for the ARLnc signature for 1-, 3-, and 5- year OS were 0.683, 0.739, and 0.618 in the training cohort and 0.671, 0.646, and 0.680 in the validation cohort, respectively. Univariate and multivariate Cox regression analyses indicated that the ARLnc signature was an independent prognostic factor for STAD patients (p < 0.001). Furthermore, the nomogram and calibration curve showed accurate prediction of the survival time based on the risk score. In addition, 262 mRNAs were screened for coexpression with four ARLncs, and GO analysis showed that mRNAs were mainly involved in biological processes, including angiogenesis, cell adhesion, wound healing, and extracellular matrix organization. Furthermore, correlation analysis showed that there was a positive correlation between risk score and the expression of the angiogenesis markers, CD34 and CD105, in TCGA datasets and our clinical sample cohort.ConclusionOur study constructed a prognostic signature consisting of four ARLnc genes, which was closely related to the survival of STAD patients, showing high efficacy of the prognostic signature. Thus, the present study provided a novel biomarker and promising therapeutic strategy for patients with STAD.
| S-EPMC8653638 | biostudies-literature