MicroRNA related genetic variation and head and neck cancer

MicroRNA相关遗传变异与头颈癌

• 批准号: 8503089
• 负责人: Brock Clarke Christensen
• 金额: $ 73.25万
• 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: 2013-09-10 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8503089
• 关键词: 3' Untranslated Regions; Alcohol consumption; Binding; Binding Sites; Biogenesis; Biological; Biological Markers; Biology; Blood; Blood specimen; Cancer Patient; Case-Control Studies; Cataloging; Catalogs; Clinical Data; Code; Custom; DNA Methylation; Data; Data Set; Diagnosis; Disease; Doctor of Medicine; Epidemiology; Functional RNA; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; Human Papillomavirus; Human papillomavirus 16; Individual; Infection; KRAS2 gene; Larynx; Linkage Disequilibrium; Literature; Malignant Neoplasms; Malignant neoplasm of pharynx; Messenger RNA; MicroRNAs; Modeling; Molecular; Oral cavity; Parents; Pathogenesis; Patients; Pharyngeal structure; Play; Population; Population Study; Predisposition; Process; Reporting; Resources; Risk; Risk Factors; Risk Marker; Role; SNP genotyping; Signal Transduction; Site; Staging; Study Subject; Survival Rate; System; Testing; Tobacco smoking; Training; Transcript; Translations; Untranslated Regions; Validation; Variant; Work; advanced disease; base; cancer diagnosis; cancer risk; cancer type; case control; disorder risk; genetic variant; genome wide association study; improved; insight; malignant mouth neoplasm; meetings; molecular marker; molecular phenotype; novel; outcome forecast; peripheral blood; population based; prognostic; public health relevance; success; tumor

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.

描述（由申请人提供）：MicroRNA相关的遗传变异和头颈癌 头颈部鳞状细胞癌（HNSCC）是一种常见的疾病，预后较差。每年在全球范围内诊断出超过40万例HNSCC病例，大多数患者患有晚期疾病。 HNSCC创世记中有一个公认的遗传易感性成分。此外，当前用于HNSCC生存的预后模型基于分期，组织病理学标准开始包括HPV评估，但缺乏强大的遗传标记。该建议将研究HNSCC风险与存活之间的关系，以及一类新的正常遗传变异，即MicroRNA相关SNP（miR-SNP）。 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方法取得了一些成功，但在GWAS面板上，miR-SNP并未得到很好的代表，并且对与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，并且快速新兴的文献已经开始证明候选miR-SNP与包括头部和颈部在内的人类癌症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HNSCC风险和预后相关的miR-SNP，然后验证HNSCC案例和对照组的独立人群中确定的关联。我们小组的先前工作表明，SNP在miRNA基因miR196A2的成熟序列中与HNSCC风险以及咽癌患者的存活率之间存在显着关联。另外，我们观察到在KRAS 3'UTR中的let-7 miRNA靶位点与口腔癌患者的存活率之间存在显着关联。此外，在有关HNSCC的miR-SNP以及风险和存活的每一个报告中，我们研究了变异基因型对miRNA和/或靶基因转录本表达的功能后果。该提议是我们初步工作的逻辑扩展，并且通过基因分型进行了18,000多个mir-SNP，将远远超出候选miR-SNP方法。在我们的最终目标中，结合了家长研究中广泛的分子数据曲目，我们将使用系统基因组学方法来探索MiR-SNP与HNSCC风险与预后之间确定关系的生物基础和功能相关性。此外，通过将miR-SNP数据与其他分子标记整合在一起，我们将进一步完善确定的风险和预后标记，以最大程度地发挥其影响和翻译潜力。