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 DNA sequencing using """"""""Next- Gen"""""""" DNA 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 hypomethylationthat 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)
Project #
Application #
Study Section
Subcommittee G - Education (NCI)
Program Officer
Okano, Paul
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
Hiken, J F; McDonald, J I; Decker, K F et al. (2017) Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer. Oncogene 36:2319-2327
Schlosberg, Christopher E; VanderKraats, Nathan D; Edwards, John R (2017) Modeling complex patterns of differential DNA methylation that associate with gene expression changes. Nucleic Acids Res 45:5100-5111
Powell, Emily; Shao, Jiansu; Yuan, Yuan et al. (2016) p53 deficiency linked to B cell translocation gene 2 (BTG2) loss enhances metastatic potential by promoting tumor growth in primary and metastatic sites in patient-derived xenograft (PDX) models of triple-negative breast cancer. Breast Cancer Res 18:13
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
Li, Shunqiang; Shen, Dong; Shao, Jieya et al. (2013) Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep 4:1116-30
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
Decker, Keith F; Zheng, Dali; He, Yuhong et al. (2012) Persistent androgen receptor-mediated transcription in castration-resistant prostate cancer under androgen-deprived conditions. Nucleic Acids Res 40:10765-79
Edwards, John R; O'Donnell, Anne H; Rollins, Robert A et al. (2010) Chromatin and sequence features that define the fine and gross structure of genomic methylation patterns. Genome Res 20:972-80