Molecular epidemiology/functional analysis of microRNAs in Non-Hodgkin's lymphoma

描述(由申请人提供)：拟议研究的重点将是确定microRNAs中与非霍奇金淋巴瘤(NHL)风险显著相关的遗传变异。我们的长期目标是确定一组miRNA SNPs，这些SNPs可能作为淋巴瘤发生的新的风险生物标记物。我们之前基于人群的非霍奇金淋巴瘤研究的存档DNA样本将用于混合遗传分析，这允许大量样本和足够的能力来检测真正的关联。还将采用miRNA克隆和基于载体的递送系统来确定所有已发现的变体对miRNA加工和下游调控能力的影响。将使用全基因组表达微阵列和遗传网络分析来询问每个与淋巴瘤相关的miRNA，以确定哪些生物途径受到miRNA功能增益的影响，并确定每个变异的影响，特别是在与淋巴瘤相关的途径的背景下。此外，每个淋巴瘤相关miRNA调控的通路将被用来确定淋巴瘤病因学中涉及的新的生物学机制，为未来在化学预防和靶向治疗方面的研究提供新的领域。到目前为止，很少有已发表的分子流行病学研究来确定miRNAs的变异是否可能与人群水平的人类癌症风险有关。拟议的多学科项目将从分子流行病学和功能遗传学的角度对miRNAs进行研究，从这些研究中获得的信息将为miRNA与癌症的联系提供基于人群的证据，并将有助于进一步了解miRNAs在肿瘤发生中的作用。由于这个项目已经有了DNA样本，拟议的研究可以在相对较短的时间内进行，并将极有效地利用时间和资源。从这项研究中获得的知识有可能：1)识别与NHL风险相关的新的生物标记物；2)促进我们对淋巴瘤发生的生物学机制的理解；3)提供新的研究途径，以促进新的化学预防和治疗策略的发展。

DESCRIPTION (provided by applicant): The focus of the proposed study will be to identify genetic variants in microRNAs which are significantly associated with risk of Non-Hodgkin's lymphoma (NHL). Our long-term goal is to identify a panel of miRNA SNPs that may serve as novel risk biomarkers in lymphomagenesis. Archived DNA samples from our previous population-based studies of NHL will be used for the pooled genetic analysis, which allows for a large sample size and sufficient power to detect genuine associations. miRNA cloning and a vector-based delivery system will also be employed to determine the impact of all identified variants on miRNA processing and downstream regulatory capacity. Each lymphoma-associated miRNA will be interrogated using whole-genome expression microarrays and genetic networking analyses, in order to determine which biological pathways are affected by miRNA gain-of-function, and to determine the impact of each variant, particularly within the context of lymphoma-relevant pathways. In addition, the pathways regulated by each lymphoma-associated miRNA will be used to identify novel biological mechanisms involved in the etiology of lymphoma, providing new areas of future research in chemoprevention and targeted therapies. To date, very few published molecular epidemiological studies have been performed to determine whether variants in miRNAs may be associated with human cancer risk at the population level. The proposed multidisciplinary project will investigate miRNAs from a molecular epidemiological and functional genetic perspective, and the information gleaned from these studies will provide population-based evidence for the miRNA-cancer connection, and will contribute significantly to furthering our understanding of the role of miRNAs in tumorigenesis. Since DNA samples are already available for this project, the proposed study can be conducted within a relatively short time period, and will represent an extremely efficient use of time and resources. The knowledge obtained from this study has the potential to: 1) identify novel biomarkers associated with NHL risk; 2) advance our understanding of the biological mechanism involved in lymphomagenesis; and 3) provide new avenues of research which can be exploited to facilitate the development of novel chemopreventive and therapeutic strategies.