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Epigenome-wide gene-age interaction study reveals reversed effects of MORN1 DNA methylation on survival between young and elderly oral squamous cell carcinoma patients.

ABSTRACT: DNA methylation serves as a reversible and prognostic biomarker for oral squamous cell carcinoma (OSCC) patients. It is unclear whether the effect of DNA methylation on OSCC overall survival varies with age. As a result, we performed a two-phase gene-age interaction study of OSCC prognosis on an epigenome-wide scale using the Cox proportional hazards model. We identified one CpG probe, cg11676291 _MORN1 , whose effect was significantly modified by age (HR_discovery = 1.018, p = 4.07 × 10^-07, FDR-q = 3.67 × 10^-02; HR_validation = 1.058, p = 8.09 × 10^-03; HR _combined = 1.019, p = 7.36 × 10^-10). Moreover, there was an antagonistic interaction between hypomethylation of cg11676291 _MORN1 and age (HR_interaction = 0.284; 95% CI, 0.135-0.597; p = 9.04 × 10^-04). The prognosis of OSCC patients was well discriminated by the prognostic score incorporating cg11676291 _MORN1 -age interaction (HR _{high vs. low} = 3.66, 95% CI: 2.40-5.60, p = 1.93 × 10^-09). By adding 24 significant gene-age interactions using a looser criterion, we significantly improved the area under the receiver operating characteristic curve (AUC) of the model at 3- and 5-year prognostic prediction (AUC_3-year = 0.80, AUC_5-year = 0.79, C-index = 0.75). Our study identified a significant interaction between cg11676291 _MORN1 and age on OSCC survival, providing a potential therapeutic target for OSCC patients.

SUBMITTER: Xu Z

PROVIDER: S-EPMC9366171 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Epigenome-wide gene-age interaction study reveals reversed effects of MORN1 DNA methylation on survival between young and elderly oral squamous cell carcinoma patients.

Xu Ziang Z Gu Yan Y Chen Jiajin J Chen Xinlei X Song Yunjie Y Fan Juanjuan J Ji Xinyu X Li Yanyan Y Zhang Wei W Zhang Ruyang R

Frontiers in oncology 20220728

DNA methylation serves as a reversible and prognostic biomarker for oral squamous cell carcinoma (OSCC) patients. It is unclear whether the effect of DNA methylation on OSCC overall survival varies with age. As a result, we performed a two-phase gene-age interaction study of OSCC prognosis on an epigenome-wide scale using the Cox proportional hazards model. We identified one CpG probe, cg11676291 MORN1 , whose effect was significantly modified by age (HRdiscovery = 1 ...[more]

PMID: 35965572

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Project description:ImportanceDepressive disorders arise from a combination of genetic and environmental risk factors. Epigenetic disruption provides a plausible mechanism through which gene-environment interactions lead to depression. Large-scale, epigenome-wide studies on depression are missing, hampering the identification of potentially modifiable biomarkers.ObjectiveTo identify epigenetic mechanisms underlying depression in middle-aged and elderly persons, using DNA methylation in blood.Design, setting, and participantsTo date, the first cross-ethnic meta-analysis of epigenome-wide association studies (EWAS) within the framework of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium was conducted. The discovery EWAS included 7948 individuals of European origin from 9 population-based cohorts. Participants who were assessed for both depressive symptoms and whole-blood DNA methylation were included in the study. Results of EWAS were pooled using sample-size weighted meta-analysis. Replication of the top epigenetic sites was performed in 3308 individuals of African American and European origin from 2 population-based cohorts.Main outcomes and measuresWhole-blood DNA methylation levels were assayed with Illumina-Infinium Human Methylation 450K BeadChip and depressive symptoms were assessed by questionnaire.ResultsThe discovery cohorts consisted of 7948 individuals (4104 [51.6%] women) with a mean (SD) age of 65.4 (5.8) years. The replication cohort consisted of 3308 individuals (2456 [74.2%] women) with a mean (SD) age of 60.3 (6.4) years. The EWAS identified methylation of 3 CpG sites to be significantly associated with increased depressive symptoms: cg04987734 (P = 1.57 × 10-08; n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 × 10-09; n = 11 256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 × 10-08; n = 11 256; chromosome = 15q26.1). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 × 10-03) and of ARHGEF3 in fibroblasts (effect, -0.48; P = 9.8 × 10-04) was associated with major depression.Conclusions and relevanceThis study identifies 3 methylated sites associated with depressive symptoms. All 3 findings point toward axon guidance as the common disrupted pathway in depression. The findings provide new insights into the molecular mechanisms underlying the complex pathophysiology of depression. Further research is warranted to determine the utility of these findings as biomarkers of depression and evaluate any potential role in the pathophysiology of depression and their downstream clinical effects.

Project description:ObjectiveThe objectives of this study were to decipher whether age-independent cardiovascular risk is associated with DNA methylation at 5'-cytosine-phosphate-guanine-3' (CpG) level and to determine whether these differential methylation signatures are associated with the incidence of cardiovascular events.Approach and resultsWe designed a 2-stage, cross-sectional, epigenome-wide association study. Age-independent cardiovascular risk calculation was based on vascular age and on the residuals of the relationship between age and cardiovascular risk. Blood DNA methylomes from 2 independent populations were profiled using the Infinium HumanMethylation450 BeadChip. The discovery stage of these studies was performed in the REGICOR cohort (REgistre GIroní del COR; n=645). Next, we validated the initial findings in the Framingham Offspring Study (n=2542). Eight CpGs located in 4 genes (AHRR, CPT1A, PPIF, and SBNO2) and 3 intergenic regions showed differential methylation in association with age-independent cardiovascular risk (P≤1.17×10-7). These CpGs explained 12.01% to 15.16% of the variability of age-independent cardiovascular risk in REGICOR and 7.51% to 8.53% in Framingham Offspring Study. Four of them were only related to smoking, 3 were related to smoking and body mass index, and 1 to diabetes mellitus, triglycerides levels, and body mass index (P≤7.81×10-4). In addition, we developed methylation risk scores based on these CpGs and observed an association between these scores and cardiovascular disease incidence (hazard ratio=1.32; 95% confidence interval: 1.16-1.51).ConclusionsAge-independent cardiovascular risk was related to different DNA methylation profiles, with 8 CpGs showing differential methylation patterns. Most of these CpGs were associated with smoking, and 3 of them were also related to body mass index. Risk scores based on these differential methylation patterns were associated with cardiovascular events and could be useful predictive indices.

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Epigenome-wide gene-age interaction study reveals reversed effects of MORN1 DNA methylation on survival between young and elderly oral squamous cell carcinoma patients.

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Epigenome-wide gene-age interaction study reveals reversed effects of <i>MORN1</i> DNA methylation on survival between young and elderly oral squamous cell carcinoma patients.

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