MicroRNA related genetic variation and head and neck cancer

描述(申请人提供)：与microRNA相关的基因变异与头颈癌 头颈部鳞状细胞癌(HNSCC)是一种常见病、多发病，预后较差。全世界每年新诊断的HNSCC病例超过40万例，大多数患者都患有晚期疾病。在HNSCC的发生中存在一个公认的、未被完全描述的遗传易感性成分。此外，目前对HNSCC生存的预后模型是基于分期和组织病理学标准的，开始包括HPV评估，但缺乏强有力的遗传标记。这项建议将调查HNSCC风险和生存与一类新的正常遗传变异-microRNA相关SNPs(miR-SNPs)之间的关系。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。几乎完全是非编码的miR-SNP显然具有关键的调节能力，迅速出现的文献已经开始证明候选miR-SNPs与人类癌症(包括头颈部癌症)的风险和预后之间的关联。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HNSCC风险和预后相关的miR-SNPs，然后在独立的HNSCC病例和对照人群中验证已确定的相关性。我们小组以前的工作已经证明了miRNA基因MIR196A2成熟序列中的SNP与HNSCC的风险以及咽癌患者的生存之间存在显著的相关性。另外，我们观察到KRAS基因3‘非编码区的let-7miRNA靶点与口腔癌患者的生存密切相关。此外，在每一篇关于miR-SNPs与HNSCC风险和生存的报道中，我们都研究了变异基因对miRNAs和/或靶基因转录本表达的功能影响。这项建议是我们前期工作的合理扩展，并将远远超出候选miR-SNP方法的范围，对18,000多个miR-SNP进行基因分型。在我们的最终目标中，结合来自亲代研究的大量分子数据，我们将使用系统基因组学方法来探索miR-SNPs与HNSCC风险和预后之间已识别的关系的生物学基础和功能相关性。此外，通过将miR-SNP数据与其他分子标记相结合，我们将进一步提炼识别的风险和预后标记，以最大限度地发挥其影响和翻译潜力。

DESCRIPTION (provided by applicant): MicroRNA related genetic variation and head and neck cancer Head and neck squamous cell carcinoma (HNSCC) is a common and often disfiguring disease with a poor prognosis. Over 400,000 new cases of HNSCC are diagnosed annually worldwide, and most patients present with advanced disease. There is a recognized and incompletely described genetic susceptibility component in HNSCC genesis. Further, current prognostic models for HNSCC survival are based on staging and histopathologic criteria, are beginning to include HPV assessment, but lack robust genetic markers. This proposal will investigate the relationship between HNSCC risk and survival and a novel class of normal genetic variation, microRNA-related SNPs (miR-SNPs). 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 including those of the head and neck. 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 risk and prognosis of HNSCC, and to then validate identified associations in an independent population of HNSCC cases and controls. Previous work from our group has demonstrated a significant association between a SNP in the mature sequence of the miRNA gene MIR196A2 and risk of HNSCC, as well as the survival of patients with pharyngeal cancer. Separately, we observed a significant association between a let-7 miRNA target site in the 3'UTR of KRAS and survival of oral cancer patients. Further, in each of these reports on miR-SNPs and risk and survival of HNSCC we investigated the functional consequences of variant genotypes on expression of miRNAs and/or target gene transcripts. This proposal is a logical extension of our preliminary work and will extend well beyond candidate miR-SNP approaches by genotyping over 18,000 miR- SNPs. In our final aim, in conjunction with an extensive repertoire of molecular data from the parent study, we will use a systems genomics approach to explore the biological underpinnings and functional relevance of identified relationships between miR-SNPs and risk and prognosis of HNSCC. In addition, by integrating miR- SNP data with other molecular markers we will further refine identified markers of risk and prognosis to maximize their impact and translational potential.