? ? Global hypomethylation, accompanied by region-specific hypermethylation, is a common characteristic among tumor cells. The occurrence of DNA methylation within the genome is not random, but rather patterns of methylation are generated that are gene and tumor type specific. How DNA methylation patterns are established is still poorly understood. Epidemiological and clinical studies provide evidence that genetic variants among the key methyl-group metabolism gene MTHFR and the de novo DNA methyltransferase gene DNMT3b in humans can lead to increased or decreased susceptibility to certain types of cancers. Because of the regulatory roles that MTHFR and DNMT3b play in the fundamental process of DNA methylation, elucidation of the molecular mechanisms underlying the interplay of genetic variations in these genes and aberrant epigenetic changes in cancer are of the utmost importance. The long term goal of this project is to understand the link between genetic variations in methylation related genes and aberrant DNA methylation changes in cancer. This project is a direct extension of a previous funded effort (Caldwell, PI, R21/R33 CA- 097880, """"""""Epigenomic Signature of non-Hodgkin's Lymphomas""""""""). Our ongoing work using methylation microarrays has discovered abnormal DNA methylation patterns in a wide spectrum of hematologic malignancies including acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL) and Multiple Myeloma (MM), and identified potential new tumor-specific biomarkers. We hypothesize that the aberrant methylation patterns observed in tumor cells are associated with certain genetic polymorphisms among methylation related genes. To test our hypothesis, we propose to evaluate the association of three polymorphisms of MTHFR and DNMT3b with global and gene-specific methylation profiles in a group of clinical samples which have been previously used for methylation study in our laboratory. Thus, we plan to analyze the polymorphisms of MTHFR and DNMT3b in 150 primary NHL and MM samples (Aim 1), and then model the relationship between global and gene-specific methylation and the polymorphisms of MTHFR and DNMT3b (Aim 2). Although epidemiological studies of genetic polymorphisms of the methylation related genes and their association with cancer risks have been conducted by various groups, little has been known about the roles of these polymorphisms in global and gene specific DNA methylation processes. The proposed study will directly apply epigenetic approaches in cancer epidemiology and is expected to provide a greater understanding of the relationship between genetic variation, global methylation patterns and regional hypermethylation of tumor suppressor genes. The systematic approach would set the stage to use the data acquired in this RO3 application as preliminary data for a larger controlled epidemiology study. ? ? ?
