Study
PLCO
(Learn more about this study)
Project ID
2010-0126
Initial CDAS Request Approval
Sep 23, 2010
Title
Risk of renal cell carcinoma in relation to global DNA methylation in peripheral blood leukocytes
Summary
Alterations in global (genome-wide) DNA methylation levels are thought to 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. 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. In a case-control study of renal cancer conducted in Central and Eastern Europe, we found that levels of LINE-1 methylation in DNA from peripheral blood lymphocytes were significantly higher in cases compared to controls. Furthermore, higher levels of LINE-1 methylation acted as a strong risk factor for renal cancer, with the association appearing to be more pronounced among current smokers. However, because these samples were collected postdiagnosis, it remains unclear whether the observed differences occurred prior to, or as a result of carcinogenesis. To elucidate this issue, in the proposed study, we will examine the relationship between global DNA methylation (LINE-1) and renal cell cancer risk using DNA from prospectively collected blood samples obtained in the PLCO Screening Trial. Using prospectively collected genomic DNA from the PLCO Screening Trial, this study will provide an invaluable opportunity to examine the role of global DNA methylation in predicting the risk of renal cancer. This study will allow us to followup leads generated in the Central and Eastern European Renal Cancer Case-Control study but with pre-diagnostic samples. Results from the proposed study will greatly expand our knowledge on the role of DNA methylation and subsequent renal cancer risk and will help us determine whether global methylation changes are associated with cancer susceptibility, or alternatively as a result of disease.
Aims
We propose to study the following specific aims in 242 renal cell cancer cases and 484 controls from a nested case-control study of renal cell cancer within the PLCO prospective cohort:
1. To evaluate the association between global methylation levels in long interspersed nucleotide elements (LINE-1) in genomic DNA and risk of renal cell cancer, and replicate findings from the Central and Eastern European Renal Cancer Study to determine whether the observed differences are also apparent prior to cancer development.
2. To explore whether the association between methylation levels and risk of renal cell cancer is modified by factors associated with oxidative stress, such as smoking and dietary variables obtained from PLCO questionnaire data.
A secondary aim of the proposed study is to identify contributing factors to variation in genome-wide methylation among controls.
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