Dataset Information

DNA methylation array analysis identifies profiles of blood-derived DNA methylation associated with bladder cancer.

ABSTRACT: Epigenetic alterations in tissues targeted for cancer play a causal role in carcinogenesis. Changes in DNA methylation in nontarget tissues, specifically peripheral blood, can also affect risk of malignant disease. We sought to identify specific profiles of DNA methylation in peripheral blood that are associated with bladder cancer risk and therefore serve as an epigenetic marker of disease susceptibility.We performed genome-wide DNA methylation profiling on participants involved in a population-based incident case-control study of bladder cancer.In a training set of 112 cases and 118 controls, we identified a panel of 9 CpG loci whose profile of DNA methylation was significantly associated with bladder cancer in a masked, independent testing series of 111 cases and 119 controls (P < .0001). Membership in three of the most methylated classes was associated with a 5.2-fold increased risk of bladder cancer (95% CI, 2.8 to 9.7), and a model that included the methylation classification, participant age, sex, smoking status, and family history of bladder cancer was a significant predictor of bladder cancer (area under the curve, 0.76; 95% CI, 0.70 to 0.82). CpG loci associated with bladder cancer and aging had neighboring sequences enriched for transcription-factor binding sites related to immune modulation and forkhead family members.These results indicate that profiles of epigenetic states in blood are associated with risk of bladder cancer and signal the potential utility of epigenetic profiles in peripheral blood as novel markers of susceptibility to this and other malignancies.

SUBMITTER: Marsit CJ

PROVIDER: S-EPMC3083868 | biostudies-other | 2011 Mar

REPOSITORIES: biostudies-other

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DNA methylation array analysis identifies profiles of blood-derived DNA methylation associated with bladder cancer.

Marsit Carmen J CJ Koestler Devin C DC Christensen Brock C BC Karagas Margaret R MR Houseman E Andres EA Kelsey Karl T KT

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20110222 9

<h4>Purpose</h4>Epigenetic alterations in tissues targeted for cancer play a causal role in carcinogenesis. Changes in DNA methylation in nontarget tissues, specifically peripheral blood, can also affect risk of malignant disease. We sought to identify specific profiles of DNA methylation in peripheral blood that are associated with bladder cancer risk and therefore serve as an epigenetic marker of disease susceptibility.<h4>Methods</h4>We performed genome-wide DNA methylation profiling on parti ...[more]

PMID: 21343564

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Project description:A subset of individuals with type 1 diabetes will develop diabetic kidney disease (DKD). DKD is heritable and large-scale genome-wide association studies have begun to identify genetic factors that influence DKD. Complementary to genetic factors, we know that a person's epigenetic profile is also altered with DKD. This study reports analysis of DNA methylation, a major epigenetic feature, evaluating methylome-wide loci for association with DKD. Unique features (n = 485,577; 482,421 CpG probes) were evaluated in blood-derived DNA from carefully phenotyped White European individuals diagnosed with type 1 diabetes with (cases) or without (controls) DKD (n = 677 samples). Explicitly, 150 cases were compared to 100 controls using the 450K array, with subsequent analysis using data previously generated for a further 96 cases and 96 controls on the 27K array, and de novo methylation data generated for replication in 139 cases and 96 controls. Following stringent quality control, raw data were quantile normalized and beta values calculated to reflect the methylation status at each site. The difference in methylation status was evaluated between cases and controls; resultant P-values for array-based data were adjusted for multiple testing. Genes with significantly increased (hypermethylated) and/or decreased (hypomethylated) levels of DNA methylation were considered for biological relevance by functional enrichment analysis using KEGG pathways. Twenty-two loci demonstrated statistically significant fold changes associated with DKD and additional support for these associated loci was sought using independent samples derived from patients recruited with similar inclusion criteria. Markers associated with CCNL1 and ZNF187 genes are supported as differentially regulated loci (P < 10-8), with evidence also presented for AFF3, which has been identified from a meta-analysis and subsequent replication of genome-wide association studies. Further supporting evidence for differential gene expression in CCNL1 and ZNF187 is presented from kidney biopsy and blood-derived RNA in people with and without kidney disease from NephroSeq. Evidence confirming that methylation sites influence the development of DKD may aid risk prediction tools and stimulate research to identify epigenomic therapies which might be clinically useful for this disease.

Dataset Information

DNA methylation array analysis identifies profiles of blood-derived DNA methylation associated with bladder cancer.

Publications

DNA methylation array analysis identifies profiles of blood-derived DNA methylation associated with bladder cancer.

Similar Datasets

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