MicroRNA Related Genetic Variation in Bladder Cancer Recurrence and Survival

膀胱癌复发和生存中 MicroRNA 相关的遗传变异

• 批准号: 8487854
• 负责人: Brock Clarke Christensen
• 金额: $ 17.59万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487854
• 关键词: 3' Untranslated Regions; Accounting; Binding; Biogenesis; Bioinformatics; Biological; Biological Markers; Bladder Neoplasm; Cancer Patient; Cancer Prognosis; Carcinoma; Case-Control Studies; Cataloging; Catalogs; Cessation of life; Cleaved cell; Clinical; Clinical Management; Cystoscopy; Development; Diagnosis; Disease; Epidemiologic Studies; Epidemiology; Expenditure; Functional RNA; General Population; Genes; Genetic; Genetic Markers; Genetic Translation; Genetic Variation; Genotype; Human; Individual; KRAS2 gene; Life; Literature; Malignant Neoplasms; Malignant neoplasm of pharynx; Malignant neoplasm of urinary bladder; Messenger RNA; MicroRNAs; Molecular; Morbidity - disease rate; Muscle; Oligonucleotides; Outcome; Parents; Patients; Play; Population Study; Process; Processed Genes; Protocols documentation; Recurrence; Regulation; Resources; Risk; Role; Single Nucleotide Polymorphism; Site; Specimen; Testing; Training; Transcript; Urothelial Cell; Variant; Visit; Work; base; cancer recurrence; case-based; clinical decision-making; cost; follow-up; genetic variant; genome wide association study; genome-wide; insight; malignant mouth neoplasm; mortality; novel; outcome forecast; population based; prognostic; public health relevance; screening; success; tool; tumor; tumorigenesis

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.

描述（由申请人提供）：在美国，与MicroRNA相关的遗传变异和膀胱癌的复发和生存率超过500,000个患者，患有诊断为膀胱癌，这种疾病将复发一半以上。复发的可能性很大，膀胱癌的临床管理包括对侵入性膀胱镜检查患者的常规筛查，导致患者的发病率明显。此外，部分原因是在疾病过程中重复侵入性膀胱镜检查，膀胱癌是人均治疗最昂贵的癌症，占近37亿美元（2001年） 在年度支出中。当前，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新型遗传变异 - 与microRNA相关的遗传变异（miR -SNP） - 用于膀胱癌复发和存活的新决定因素。 miR-SNP包括参与miRNA生物发生和加工的基因中mRNA转录物，miRNA基因中的miRNA靶位点的变化。尽管GWAS方法取得了一定的成功，但在GWAS面板上，mir-SNP并未得到很好的代表，并且对miRNA相关的自然遗传变异的理解非常有限。 miR-SNP几乎完全没有编码，显然具有关键的调节能力，尽管在膀胱癌的研究中存在差距，但迅速的文献已经开始证明候选mir-SNP与人类癌的风险和预后之间的关联。 miRNA目标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，可用于人群研究中的假设检验。这项工作的主要目的是利用经过验证的流行病学资源来识别与膀胱癌复发和生存相关的miR-SNP。我们的小组已经完成了一项基于地理定义的基于人群的流行病学研究，其中包括对患者复发和生存的全面评估。据我们所知，这是美国唯一的研究，也是全世界为数不多的关于膀胱癌预后决定因素的普通人群的推论之一。通过基因分型，超过18,000个miR-SNP，我们的方法将远远超出候选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，这将有助于开发临床决策工具，以根据他们的复发可能性将患者分类为随访组。通过这种方式，我们旨在通过改变膀胱癌管理的当前范式来最大程度地发挥我们所鉴定的标记物的影响和翻译潜力，降低患者的发病率和死亡率，并减少常规膀胱镜检查的成本负担。