Longitudinal Study of DNA Methylation of Inflammatory Genes and Cancer Risk (original) (raw)
Related papers
Longitudinal Study of Leukocyte DNA Methylation and Biomarkers for Cancer Risk in Older Adults
2019
Background: Changes in DNA methylation over the course of life may provide an indicator of risk for cancer. We explored longitudinal changes in CpG methylation from blood leukocytes, and likelihood of a future cancer diagnosis. Methods: Peripheral blood samples were obtained at baseline and at follow-up visit from 20 participants in the Health, Aging and Body Composition prospective cohort study. Genome-wide CpG methylation was assayed using the Illumina Infinium Human MethylationEPIC (HM850K) microarray. Results: Global patterns in DNA methylation from CpG-based analyses showed extensive changes in cell composition over time in participants who developed cancer. By visit year 6, the proportion of CD8+ T-cells decreased (p-value = 0.02), while granulocytes cell levels increased (p-value = 0.04) among participants diagnosed with cancer compared to those who remained cancer-free (cancer-free vs. cancer-present: 0.03 ± 0.02 vs. 0.003 ± 0.005 for CD8+ T-cells; 0.52 ± 0.14 vs. 0.66 ± 0.0...
International journal of cancer, 2017
The association between aging and cancer is complex. Recent studies have developed measures of biological aging based on DNA methylation and called them "age acceleration." We aimed to assess the associations of age acceleration with risk of and survival from seven common cancers. Seven case-control studies of DNA methylation and colorectal, gastric, kidney, lung, prostate and urothelial cancer and B-cell lymphoma nested in the Melbourne Collaborative Cohort Study were conducted. Cancer cases, vital status and cause of death were ascertained through linkage with cancer and death registries. Conditional logistic regression and Cox models were used to estimate odds ratios (OR) and hazard ratios (HR) and 95% confidence intervals (CI) for associations of five age acceleration measures derived from the Human Methylation 450 K Beadchip assay with cancer risk (N = 3,216 cases) and survival (N = 1,726 deaths), respectively. Epigenetic aging was associated with increased cancer ris...
DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases
Genome biology, 2016
Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 × 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%...
Journal of Internal Medicine, 2007
Objective. The lifespan of dialysis patients is as short as in patients with metastatic cancer disease, mainly due to cardiovascular disease (CVD). DNA methylation is an important cellular mechanism modulating gene expression associated with ageing, inflammation and atherosclerotic processes.Design. DNA methylation was analysed in peripheral blood leucocytes from three different groups of chronic kidney disease (CKD) populations (37 CKD stages 3 and 4 patients, 98 CKD stage 5 patients and 20 prevalent haemodialysis patients). Thirty-six healthy subjects served as controls. Clinical characteristics (diabetes mellitus, nutritional status and presence of clinical CVD), inflammation and oxidative stress biomarkers, homocysteine and global DNA methylation in peripheral blood leucocytes (defined as HpaII/MspI ratio by the Luminometric Methylation Assay method) were evaluated. CKD stage 5 patients (n = 98) starting dialysis treatment were followed for a period of 36 ± 2 months.Results. Inflamed patients had lower ratios of HpaII/MspI, indicating global DNA hypermethylation. Analysis by the Cox regression model demonstrated that DNA hypermethylation (HpaII/MspI ratio <median) was significantly associated with both all-cause (RR 5.0; 95% CI: 1.7–14.8; P < 0.01) and cardiovascular (RR 13.9; 95% CI: 1.8–109.3; P < 0.05) mortality, even following the adjustment for age, CVD, diabetes mellitus and inflammation.Conclusion. The present study demonstrates that global DNA hypermethylation is associated with inflammation and increased mortality in CKD.
2020
Pancreatic cancer is projected to become the second most common cause of cancer death over the next 5 years. Since inflammation is thought to be a common trajectory for disease initiation, we sought to prospectively characterize immune profiles using DNA methylation markers to examine whether they play a key role in pancreatic cancer risk. In a nested case-control study pooling three U.S. prospective cohort studies, DNA methylation was measured in prediagnostic leukocytes of incident pancreatic cancer cases and matched controls using the Illumina MethylationEPIC array. Differentially methylated regions were used to predict immune cell types and CpGs previously associated with blood inflammatory markers were selected for the analysis. DNA methylation data from a retrospective case-control study conducted in Spain (PanGenEU) was used for independent replication of results. Immune cell proportions and ratio of cell proportions were not associated with pancreatic cancer risk in the nest...
DNA methylation of oxidative stress genes and cancer risk in the Normative Aging Study
Oxidative stress (OS) is a primary mechanism of carcinogenesis, and methylation of genes related to it may play a role in cancer development. In this study, we examined the prospective association between blood DNA methylation of four oxidative stress genes and cancer incidence. Our study population included a total of 582 participants in the Normative Aging Study (NAS) who had blood drawn during 1-4 visits from 1999-2012 (mean follow up 9.0 years). Promoter DNA methylation of CRAT, iNOS, OGG1 and GCR in blood leukocytes was measured using pyrosequencing. We used Cox regression models to examine prospective associations between cancer incidence and both methylation at the baseline visit and methylation rate of changes over time. Baseline OGG1 methylation was associated with higher risk of all-cancer (HR: 1.43, 95% CI: 1.15-1.78) and prostate cancer (HR: 1.52, 95% CI: 1.03-2.25) incidence. Compared with participants remaining cancer-free, those who eventually developed cancer had significantly accelerated CRAT methylation (p = 0.04) and decelerated iNOS methylation (p<0.01) over time prior to cancer diagnosis. Accelerated CRAT methylation was associated with higher all-cancer incidence (HR: 3.88, 95% CI: 1.06-14.30), whereas accelerated iNOS methylation was associated with lower all-cancer incidence (HR: 0.08, 95% CI 0.02-0.38). Our results suggest that methylation and its dynamic change over time in OS-related genes, including OGG1, CRAT and iNOS, may play an important role in carcinogenesis. These results can potentially facilitate the development of early detection biomarkers and new treatments for a variety of cancers.
2021
Epigenetic alterations such as DNA methylation have been associated with the etiology of inflammation-related diseases. The present study evaluated the association between the methylation levels of LPL , ADRB3 and MTHFR genes and the stage of inflammation in individuals with isolated or associated morbidities, as well as in individuals without morbidities. This is a cross-sectional population-based study, in which 261 adults, between 20 and 59 years, individuals of both sex were selected. Inflammatory parameters were evaluated in blood, and the evaluation of methylation levels in the promoter of LPL , ADRB3 and MTHFR genes was performed in peripheral blood leukocytes. For statistical treatment, normality analysis was performed using the Lilliefors test, multiple linear regression, in addition to odds ratio. For all tests, the significance level adopted was 5%. In individuals with isolated morbidities, a positive association was observed between CRP values (2.49mg/L±3.7) and LPL ge...
2021
Neuromedin U (NMU) is a neuropeptide involved in gut-brain axis, energy balance and immune response. We aimed at analysing the association between NMU epigenetic variability and metabolic indices and the potential mediating role of low-grade inflammation in a general population of Italian adults. <i>NMU</i> Blood DNA methylation levels at two CpG islands (<i>NMU76</i> and <i>NMU32</i>) were analysed using pyrosequencing in a randomly selected sub-cohort of 1,160 subjects from the Moli-sani study (≥35years; 49.20% men). Multivariable regressions adjusted for age, sex, smoking, alcohol and vegetable consumption were performed to estimate the associations between methylation and metabolic phenotypes (BMI, waist-to-hip ratio, blood pressure, glucose, HOMA-IR, lipids, lipoprotein(a) and apolipoproteins). Mediation analysis was performed to identify the influence of low-grade inflammation in the association using a composite index based on C reactive pr...
Biological aging measures based on blood DNA methylation and risk of cancer: a prospective study
medRxiv (Cold Spring Harbor Laboratory), 2020
We previously investigated the association between five 'first-generation' measures of epigenetic aging and cancer risk in the Melbourne Collaborative Cohort Study. The present study assesses cancer risk associations for three recently developed methylation-based measures of aging: PhenoAge, GrimAge, and predicted telomere length. We estimated rate ratios (RRs) for risk of colorectal (N=814), gastric (N=166), kidney (N=139), lung (N=327), mature B-cell (N=426), prostate (N=847) and urothelial (N=404) cancer, using conditional logistic regression models. We observed relatively strong associations of PhenoAge with risk of colorectal, kidney, lung, mature B-cell, and urothelial cancers (RR per standard deviation ~ 1.2-1.3). Similar findings were obtained for GrimAge, but the association with lung cancer risk was remarkably stronger (RR ~ 1.8 after adjustment for smoking status, pack-years, starting age, time since quitting and other cancer risk factors). The methylation-based measures PhenoAge and GrimAge may provide insights into the relationship between biological aging and cancer.
Cancer Epidemiology Biomarkers & Prevention
Background: The peripheral blood neutrophil-to-lymphocyte ratio (NLR) is a cytologic marker of both inflammation and poor outcomes in patients with cancer. DNA methylation is a key element of the epigenetic program defining different leukocyte subtypes and may provide an alternative to cytology in assessing leukocyte profiles. Our aim was to create a bioinformatic tool to estimate NLR using DNA methylation, and to assess its diagnostic and prognostic performance in human populations. Methods: We developed a DNA methylation-derived NLR (mdNLR) index based on normal isolated leukocyte methylation libraries and established cell-mixture deconvolution algorithms. The method was applied to cancer case-control studies of the bladder, head and neck, ovary, and breast, as well as publicly available data on cancer-free subjects. Results: Across cancer studies, mdNLR scores were either elevated in cases relative to controls, or associated with increased hazard of death. High mdNLR values (>5) were strong indicators of poor survival. In addition, mdNLR scores were elevated in males, in nonHispanic white versus Hispanic ethnicity, and increased with age. We also observed a significant interaction between cigarette smoking history and mdNLR on cancer survival. Conclusions: These results mean that our current understanding of mature leukocyte methylomes is sufficient to allow researchers and clinicians to apply epigenetically based analyses of NLR in clinical and epidemiologic studies of cancer risk and survival. Impact: As cytologic measurements of NLR are not always possible (i.e., archival blood), mdNLR, which is computed from DNA methylation signatures alone, has the potential to expand the scope of epigenome-wide association studies. Cancer Epidemiol Biomarkers Prev; 26(3); 328-38. Ó2016 AACR.