MicroRNA Related Genetic Variation in Bladder Cancer Recurrence and Survival

描述（由申请人提供）：MicroRNA相关的遗传变异和膀胱癌复发和存活在美国，超过50万人患有膀胱癌，这种疾病超过一半的病例会复发。由于复发的可能性很高，膀胱癌的临床管理包括对患者进行侵入性膀胱镜检查的常规筛查，导致患者发病率显著增加。此外，部分由于侵入性膀胱镜检查在疾病过程中反复进行，膀胱癌是人均治疗费用最高的癌症，占近37亿美元（2001年美元） 年度支出。目前缺乏临床使用的决定因素，可以告知复发和生存的风险。在这里，我们建议系统地研究一类新的遗传变异-microRNA相关的遗传变异（miR-SNPs）-膀胱癌复发和生存的新决定因素。MiR-SNP包括mRNA转录物上miRNA靶位点的变异、miRNA基因中的SNP以及参与miRNA生物发生和加工的基因中的SNP。虽然GWAS方法已经取得了一些成功，但miR-SNP在GWAS面板上还没有得到很好的代表，并且对miRNA相关的自然遗传变异的理解非常有限。几乎完全非编码的miR-SNP显然具有关键的调节能力，并且迅速出现的文献已经开始证明候选miR-SNP与人类癌症的风险和预后两者之间的关联，尽管在膀胱癌的研究中存在空白。miRNA靶位点预测的最新和持续进展允许对miR-SNP进行更全面的编目和表征，可用于群体研究中的假设检验。这项工作的主要目的是利用已证实的流行病学资源来确定与膀胱癌复发和生存相关的miR-SNPs。我们的研究小组已经完成了一项以地理为基础的、以人群为基础的膀胱癌流行病学研究，包括对患者复发率和生存率的全面评估。据我们所知，这是美国唯一的同类研究，并且是世界范围内少数几个可以对一般人群进行关于膀胱癌预后决定因素的推断的方法之一。我们的方法将通过对超过18，000个miR-SNP进行基因分型而远远超出候选miR-SNP方法。我们建议确定一类新的膀胱癌复发和生存的遗传标记，这将有助于临床决策工具的发展，根据患者复发的可能性将其分为随访组。通过这种方式，我们的目标是最大限度地发挥我们所确定的标志物的影响和转化潜力，降低患者的发病率和死亡率，并通过改变目前膀胱癌管理的模式来降低常规膀胱镜检查的成本负担。

DESCRIPTION (provided by applicant): MicroRNA related genetic variation and bladder cancer recurrence and survival Over 500,000 individuals in the U.S. are living with a diagnosis of bladder cancer, a disease where over half of cases will recur. With a high likelihood of recurrence, the clinical management of bladder cancer includes routine screening of patients with invasive cystoscopy, resulting in significant patient morbidity. Further, in part because invasive cystoscopy is repeated over the course of disease, bladder cancer is the most expensive cancer to treat per capita, accounting for nearly 3.7 billion U.S. dollars (2001 dollars) in annual expenditures. Currently there is a lack of clinically used determinants that can inform on the risk of recurrence and survival. Here, we propose to systematically investigate a novel class of genetic variation - microRNA-related genetic variation (miR-SNPs) - for new determinants of bladder cancer recurrence and survival. MiR-SNPs include variation in miRNA target sites on mRNA transcripts, SNPs in miRNA genes, and SNPs in genes that participate in miRNA biogenesis and processing. While GWAS approaches have had some success, miR- SNPs have not been well represented on GWAS panels, and there is a very limited understanding of miRNA- related natural genetic variation. Almost exclusively non-coding, miR-SNPs clearly have critical regulatory capacity and the rapidly emerging literature has begun to demonstrate associations between candidate miR- SNPs and both risk and prognosis of human cancers, though there is a gap in the study of bladder cancers. Recent and continued advances in miRNA target site prediction allows a more comprehensive cataloging and characterization of miR-SNPs that can be used for hypothesis testing in population studies. The primary aim of this work is to use proven epidemiologic resources to identify miR-SNPs associated with recurrence and survival of bladder cancer. Our group has completed a geographically defined, population-based epidemiologic study of bladder cancer that includes a comprehensive assessment of patient recurrences and survival. To our knowledge this is the only study of its kind in the U.S., and one of the few worldwide from which inferences of the general population can be made regarding the determinant of bladder cancer prognosis. Our approach will extend well beyond candidate miR-SNP approaches by genotyping over 18,000 miR-SNPs. We propose to identify a new class of genetic markers of bladder cancer recurrence and survival that will contribute to the development of clinical decision-making tools to stratify patients into follow-up groups based on their likelihood of recurrence. In this way we aim to maximize the impact and translational potential of our identified markers, reduce patient morbidity and mortality, and decrease the cost burden of routine cystoscopy by shifting the current paradigm of bladder cancer management.