Understanding the role of methylation abnormalities undergone by cancer cell genomes is of great importance to cancer research and treatment;however, one major limitation has been the lack of a method for analyzing the methylation patterns of the entire genome simultaneously in a rapid, cost-effective manner. For instance, array based techniques cannot be used to reveal the methylation status of repetitive elements, which are hypothesized to play a key function in the altered expression patterns and rearrangements found in cancer cells. In particular, the role of methylation in breast cancer is still poorly understood;both hypermethylation of tumor suppressor gene promoters and global hypomethylation of the genome are thought to play significant early roles. The novel method presented here combines new techniques of fractionation of DNA according to methylation status and ultra-high throughput DMA sequencing using "Next- Gen" DMA sequencing technologies to allow efficient whole-genome methylation profiling even when only microgram amounts of DNA are available. We will use this technology to examine the complete genomic methylation status of a panel of breast cancer samples and study how these patterns correlate with various factors such as survival and recurrence to develop methylation profiles as a potentially powerful biomarker. We will use this data as a platform to elucidate the role methylation plays in breast cancer as a regulatory agent. We will determine if the hypomethylation that characterizes breast cancer is a stochastic or directed process and examine whether tumor suppressor hypermethylation is a key factor in breast cancer or if this is solely a sporadic event. We will also examine the effects of methylation on hotspots for chromosomal rearrangements, which are commonly found in breast cancer. This project, via a whole genome methylation profiling method that is unbiased and capable of investigating the methylation status of all sequences including the repeated sequences known to be demethylated in breast cancer, will provide a first look into the complete methylation landscape of breast cancer and provide new insights into epigenetic abnormalities in cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Transition Award (R00)
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Subcommittee G - Education (NCI)
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Okano, Paul
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Lund, Kirstin; Cole, John J; VanderKraats, Nathan D et al. (2014) DNMT inhibitors reverse a specific signature of aberrant promoter DNA methylation and associated gene silencing in AML. Genome Biol 15:406
Vanderkraats, Nathan D; Hiken, Jeffrey F; Decker, Keith F et al. (2013) Discovering high-resolution patterns of differential DNA methylation that correlate with gene expression changes. Nucleic Acids Res 41:6816-27