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Global DNA Hypomethylation and Telomere Shortening as Independent Risk Factors for Bladder Cancers

Principal Investigator
Name
Lee Moore
Degrees
-
Institution
NCI, DCEG, OEEB
Position Title
-
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2007-0223
Initial CDAS Request Approval
Dec 20, 2007
Title
Global DNA Hypomethylation and Telomere Shortening as Independent Risk Factors for Bladder Cancers
Summary
Most mechanistic cancer research has focused on direct DNA damage through mutations and chromosomal alterations from environmental exposures. More recent findings suggest that epigenetic alterations in the genome, such as aberrant DNA methylation and histone acetylation, also promote carcinogenesis by weakening chromosomal stability and altering normal gene expression patterns. Changes in the epigenome are believed to be early events in cancer and recently have been used as early biomarkers of disease. Hypermethylation of CpG islands in the promoter regions of more than 60 genes has been observed in cancer, implicating methylation associated gene transcriptional silencing in carcinogenesis. Genome-wide cytosine hypomethylation occurs primarily in repetitive sequences of DNA that have no obvious impact on gene expression; however, they can also occur in oncogenes that would normally be methylated and silenced. Such hypomethylation is thought to impact the integrity of the genome and has been associated with chromosomal instability resulting in gross chromosomal alterations. In a case-control study of bladder cancer conducted in Spain, we found that cytosine methylation was significantly reduced in cases compared to controls (Moore et al, submitted). Moreover, genomic hypomethylation of blood cell DNA acted as an independent risk factor for bladder cancer. A significant interaction with smoking was observed. In the proposed study, we will examine the relationship between genomic DNA hypomethylation and bladder cancer risk using prospectively collected lymphocyte DNA samples obtained in the PLCO screening trial. Using prospectively collected genomic DNA from the PLCO cohort, this study will provide an invaluable opportunity to examine the role of genomic instability, including DNA hypomethylation and telomere shortening, in predicting the risk of bladder cancer. This study will allow us to follow-up leads on these markers generated in the Spanish Bladder Cancer Case-Control study. Results from the proposed study will make a major contribution to understanding the link between pre-diagnostic genomic instability and subsequent cancer risks.
Aims

The specific aims of the proposed study are: 1. To examine association between genome-wide hypomethylation in genomic DNA from bladder cancer case and controls, to follow-up findings from the Spanish Bladder Cancer Case-Control Study. 2. Identify contributing factors to variation in genome methylation and telomere length levels among cases and controls using pre-diagnostic, prospectively collected genomic DNA samples and assess interaction between DNA methylation levels with smoking and dietary variables using PLCO questionnaire data. 3. Using existing genotyping data from CGEMS, identify genetic risk factors for selected SNPs associated with global methylation levels using existing GWAS data.

Collaborators

Stephen Chanock (CGF, NCI)
Wong-Ho Chow (NCI, DCEG)
Montse Garcia-Closas (NCI, DCEG)
Lee Moore (NCI, DCEG)
Ruth M Pfeiffer (NCI, DCEG)
Cristina Poscablo (NCI, DCEG)
Nathaniel Rothman (NCI, DCEG)
Debra Silverman (NCI, DCEG)

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