Integrated Genetic and Epigenetic Biomarkers for Molecular Epidemiology

描述(由申请人提供)： 全局性低甲基化伴随区域特异性高甲基化是肿瘤细胞的共同特征。基因组中DNA甲基化的发生不是随机的，而是产生特定于基因和肿瘤类型的甲基化模式。DNA甲基化模式是如何建立的仍然知之甚少。流行病学和临床研究表明，人类关键的甲基组代谢基因MTHFR和从头DNA甲基转移酶基因Dnmt3b之间的遗传变异可导致某些类型癌症的易感性增加或降低。由于MTHFR和DNMT3b在DNA甲基化的基本过程中起着调节作用，因此阐明这些基因中的遗传变异和癌症中异常的表观遗传变化相互作用的分子机制是至关重要的。该项目的长期目标是了解癌症中甲基化相关基因的遗传变异和DNA甲基化异常变化之间的联系。该项目是先前资助的工作(考德威尔，PI，R21/R33 CA-097880，“非霍奇金淋巴瘤的表观基因组特征”)的直接延伸。我们正在进行的使用甲基化微阵列的工作已经在包括急性淋巴细胞白血病(ALL)、非霍奇金淋巴瘤(NHL)和多发性骨髓瘤(MM)在内的广泛的血液系统恶性肿瘤中发现了异常的DNA甲基化模式，并发现了潜在的新的肿瘤特异性生物标志物。我们假设，在肿瘤细胞中观察到的异常甲基化模式与甲基化相关基因之间的某些遗传多态有关。为了验证我们的假设，我们建议评估MTHFR和Dnmt3b的三个多态与全球甲基化和基因特异性甲基化之间的关系，在我们实验室以前用于甲基化研究的一组临床样本中。因此，我们计划分析150例原发NHL和MM样本中MTHFR和Dnmt3b的多态性(目标1)，然后建模全局甲基化和基因特异性甲基化与MTHFR和Dnmt3b多态的关系(目标2)。虽然不同的群体已经对甲基化相关基因的遗传多态及其与癌症风险的关系进行了流行病学研究，但对这些多态在全球和基因特异性DNA甲基化过程中的作用知之甚少。这项拟议的研究将直接将表观遗传学方法应用于癌症流行病学，并有望更好地理解肿瘤抑制基因的遗传变异、全球甲基化模式和区域高甲基化之间的关系。系统化的方法将为使用在R03应用中获得的数据作为更大规模受控流行病学研究的初步数据奠定基础。

DESCRIPTION (provided by applicant): 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.