DNA methylation of oxidative stress genes and cancer risk in the Normative Aging Study (original) (raw)
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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...
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.
From aging to cancer: a DNA methylation journey
Ageing Research, 2012
Epigenetic gene silencing through DNA promoter hypermethylation is now recognised<strong> </strong>as a major step in the neoplastic transformation of the cell. The methylation levels of several genes increase with age in normal tissues such as the prostate or colon. Genes like <em>WRN </em>or<em> LMNA </em>that are involved in progeria,a premature aging disease <em>WRN and LMNA, </em>are epigenetically inactivated in cancer. In both aging and cancer, global DNA methylation decreases, potentially accounting for the characteristic genomic instability of these processes. In this review, we will focus on how the accumulation of changes in DNA methylation during aging impact tumourigenesis.
DNA Methylation in Cancer and Aging
Cancer Research, 2016
DNA methylation is known to be abnormal in all forms of cancer, but it is not really understood how this occurs and what is its role in tumorigenesis. In this review, we take a wide view of this problem by analyzing the strategies involved in setting up normal DNA methylation patterns and understanding how this stable epigenetic mark works to prevent gene activation during development. Aberrant DNA methylation in cancer can be generated either prior to or following cell transformation through mutations. Increasing evidence suggests, however, that most methylation changes are generated in a programmed manner and occur in a subpopulation of tissue cells during normal aging, probably predisposing them for tumorigenesis. It is likely that this methylation contributes to the tumor state by inhibiting the plasticity of cell differentiation processes. Cancer Res; 76(12); 3446-50. Ó2016 AACR.
DNA methylation and carcinogenesis
Biochemistry (Moscow), 2001
The hypothesis of the exclusively genetic origin of cancer ("cancer is a disease of genes, a tumor without any dam age to the genome does not exist") dominated in the oncology until recently. A considerable amount of data confirming this hypothesis was accumulated during the last quarter of the last century. It was demonstrated that the accumulation of damage to specific genes lies in the origin of a tumor and its following progression. The damage gives rise to structural changes in the respective proteins and, consequently, to inappropriate mitogenic stimulation of cells (activation of oncogenes) or to the inac tivation of tumor suppressor genes that inhibit cell division, or to the combination of both (in most cases). According to an alternative (epigenetic) hypothesis that was extremely unpopular until recently, a tumor is caused not by a gene damage, but by an inappropriate function of genes ("cancer is a disease of gene regulation and differentiation"). However, recent studies led to the convergence of these hypotheses that initially seemed to be contradictory. It was established that both factorsgenetic and epigenetic-lie at the origin of carcinogenesis. The relative contribution of each varies significantly in different human tumors. Suppressor genes and genes of repair are inactivated in tumors due to their damage or methylation of their promoters (in the latter case an "epimutation", an epigenetic equivalent of a mutation, occurs, producing the same functional consequences). It is becoming evident that not only the mutagens, but various factors influencing cell metabolism, notably methylation, should be considered as carcinogens.
Cancer Research
DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N ¼ 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 Â 10 À7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARH-GAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. Significance: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.