DNA Methylation Array Analysis Identifies Profiles of Blood-Derived DNA Methylation Associated With Bladder Cancer

Abstract

A B S T R A C T PurposeEpigenetic 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. MethodsWe performed genome-wide DNA methylation profiling on participants involved in a populationbased incident case-control study of bladder cancer. ResultsIn 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 Ͻ .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. ConclusionThese 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.

A DNA methylation fingerprint of 1628 human samples

“…Other uses might follow, and they will require further development, such as our finding of a distinct DNA methylation fingerprint between local liver metastases and distant brain metastases derived from colorectal tumors that might suggest the use of DNA methylation patterns to predict the metastatic spectrum of a given cancer. We would also like to highlight another promising step in the clinical-benefits direction by the recent finding of 27,000 CpG-site DNA methylation profiles in blood that are associated with bladder cancer risk (Marsit et al 2011).…”

Is There a Link Between Genome-Wide Hypomethylation in Blood and Cancer Risk?

“…Furthermore, hypermethylation of BRCA1 is reportedly associated with increased prevalence of BRCA1-methylated breast tumors (65,66), suggesting a functional link between blood detectable DNA methylation and disease histology (67)(68)(69). High-throughput discovery studies have identified cancerassociated DNA methylation signatures in blood of patients with breast (69), ovarian (68), bladder (67), and head and neck cancers (70), providing potential cancer diagnostic biomarkers.…”

DNA methylation array analyses identified breast cancer‐associated HYAL2 methylation in peripheral blood

“…10 Given the accessibility of methodology, 11,12 genome-wide methylation analyses have been extended to peripheral blood in case-control studies of ovarian, bladder and head and neck cancers. [13][14][15] A few aberrant methylation patterns in peripheral blood have also been reported in BC by candidate gene approaches. [16][17][18][19] Recently, Xu et al reported an extensive blood-based epigenome-wide association study of BC by Illumina 27K Methylation Array in a well-designed prospective sister study cohort, and demonstrated that the methylation profiling of blood are promising markers for BC detection and risk evaluation.…”