Non-Hodgkin's lymphoma (NHL) is the fifth most common malignancy in the United States, accounting for an estimated 55,000 new cases and 26,000 deaths in the year 2001. Although advances in cancer treatment over the past several decades have improved outcomes for many patients with hematologic malignancies, most patients with NHL relapse and ultimately die from their disease. The challenge remains to develop targeted therapies that are both more effective and less toxic. The overall goal of this application is to further develop and test an innovative microarray tool to determine DNA methylation of CpG island promoters and 1st exon regions of important genes that affect transcriptional silencing, but may potentially be reversible by pharmacological demethylation therapies. This microarray chip can measure both DNA methylation and gene expression, and hence can provide direct evidence of methylation-dependent gene silencing and reversal. Another innovation includes development of a laboratory information system for DNA methylation based on a data model and schema compliant with an evolving international consensus on microarray standards. This will provide robust and flexible data storage and XML-tagged information sharing options for further collaborative investigations. We propose to merge epigenomic and computational technologies that can form a valuable clinical laboratory tool for assessment of NHLs. An interdisciplinary team will apply computational research methods to leverage the biomedical content to identify novel and highly selective lymphoma-related epigenetic changes in specific CpG islands that may affect gene function, and furthermore, may be potentially reversed by pharmacologic interventions. The new microarrays and computational tools developed will be widely shared among other investigators around the world. One of the greatest intellectual challenges to investigations such as this is to extract the fullest meanings and implications of all available data. The 1-year R21 phase demonstrates the proof-of-concept using 2 classes of indolent NHLs and provides quantifiable, defined milestones. The 4-year R33 phase will further enhance the microarray system, examine additional classes of indolent NHLs, and determine an Epigenomic Signature of Lymphomas to improve classification, prognostic prediction, and potentially therapeutic choices in human NHL that can improve on clinical outcomes.
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