MicroRNA Related Genetic Variation in Bladder Cancer Recurrence and Survival

描述(申请人提供)：与microRNA相关的基因变异与膀胱癌复发和存活率在美国有超过50万人被诊断患有膀胱癌，超过一半的病例会复发。由于膀胱癌复发的可能性很高，临床处理包括对患者进行常规的侵袭性膀胱镜检查，从而导致显著的患者发病率。此外，部分原因是由于侵入性膀胱镜检查在整个病程中重复进行，膀胱癌是人均治疗费用最高的癌症，占人均近37亿美元(2001美元)。 在年度支出中。目前，缺乏临床上使用的决定因素，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相关遗传变异(miR-SNPs)-膀胱癌复发和生存的新决定因素。MiR-SNPs包括转录产物上miRNA靶点的变异，miRNA基因中的SNPs，以及参与miRNA生物发生和加工的基因中的SNPs。虽然GWAS方法已经取得了一些成功，但miR-SNPs还没有很好地在GWAS小组中得到代表，而且对miRNA相关的自然遗传变异的了解非常有限。几乎完全非编码的miR-SNPs显然具有关键的调控能力，而且迅速涌现的文献已经开始证明候选miR-SNPs与人类癌症的风险和预后之间的关联，尽管在膀胱癌的研究中还存在空白。在miRNA靶点预测方面的最新和持续的进展使得能够更全面地对miR-SNPs进行编目和表征，从而可以用于人口研究中的假设检验。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。我们小组已经完成了一项关于膀胱癌的地理定义、基于人群的流行病学研究，其中包括对患者复发和存活率的全面评估。据我们所知，这是美国唯一的此类研究，也是世界上为数不多的可以从普通人群中推断膀胱癌预后决定因素的研究之一。我们的方法将远远超越候选的miR-SNP方法，对18,000个miR-SNP进行基因分型。我们建议确定一类新的膀胱癌复发和生存的遗传标志物，这将有助于开发临床决策工具，根据患者复发的可能性将患者分成随访组。通过这种方式，我们的目标是最大限度地发挥我们确定的标志物的影响和翻译潜力，降低患者的发病率和死亡率，并通过改变目前的膀胱癌治疗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.