Integrated Analysis of Germline and Somatic Mutations in Young, Low-Risk and Older, High-Risk Oral Cavity Cancer

年轻、低风险和老年、高风险口腔癌种系和体细胞突变的综合分析

• 批准号: 9788306
• 负责人: Steven Bennett Chinn
• 金额: $ 25.05万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788306
• 关键词: Age; Alcohol abuse; Alcohol consumption; Bioinformatics; CRISPR/Cas technology; Candidate Disease Gene; Cell Line; Copy Number Polymorphism; DNA Repair; Data; Data Analyses; Databases; Development; Development Plans; Diagnostic; Disease; Dyskeratosis Congenita; Education; Epidemiology; Etiology; Event; Exposure to; Family; Family history of; Fanconi' s Anemia; Female; Frequencies; Functional disorder; Funding; Gene Mutation; Genes; Genetic; Genome; Genomic Instability; Genomics; Germ-Line Mutation; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; Human Genetics; Human Papillomavirus; In Vitro; Inherited; Joints; K-Series Research Career Programs; Knowledge; Malignant Neoplasms; Mentors; Mentorship; Methods; Molecular; Mutation; Oral; Oral cavity; Pathogenesis; Pathway interactions; Patient Care; Patients; Phenotype; Population; Predisposition; RNA Splicing; Recording of previous events; Research; Research Design; Research Personnel; Risk; Risk Factors; Role; Scientist; Somatic Mutation; Suggestion; Surgical Oncologist; Syndrome; Techniques; Technology; Telomerase; Telomere Maintenance; Telomere Maintenance Gene; The Cancer Genome Atlas; Tobacco use; Training; Translating; Translational Research; Variant; Viral; actionable mutation; base; cancer genetics; cancer genomics; carcinogenesis; career development; cohort; design; exome sequencing; experience; genome editing; head and neck cancer patient; head impact; high risk; high risk behavior; improved; in vitro Model; insight; keratinocyte; malignant mouth neoplasm; member; mortality; mouth squamous cell carcinoma; new therapeutic target; next generation; next generation sequencing; non-smoker; novel; older patient; oncology program; programs; skills; targeted treatment; therapy design; tobacco abuse; tobacco exposure; tool; transcriptome; transcriptome sequencing; transcriptomics; tumor; tumorigenesis; tumorigenic

PROJECT SUMMARY/ABSTRACT Oral cavity squamous cell carcinoma (OCSCC) is an aggressive and deadly disease. While tobacco and alcohol abuse are the risk factors of carcinogenesis in traditional high-risk OCSCC patients, there is a subset of young patients, even in the absence of these risk factors, who develop sporadic OCSCC. The cause of OCSCC in young patients remains unknown and despite their young age and lack of risk factors have poor survival. Based on our preliminary data, there appears to be demographic, etiologic, and mutational burden differences between younger, low-risk (≤40 years, non-smokers and non-drinkers) and traditional, high-risk (>50 years, >20 pack-years of tobacco use and high alcohol use) patients. We are seeking to utilize genomic and transcriptomic differences to determine the molecular mechanism of tumorigenesis with a focus on DNA repair and telomere maintenance pathways in young, low-risk OCSCC. The proposed study and training aims are to develop a career development plan that will be critical to further defining the molecular mechanisms of tumorigenesis through next generation sequencing in young OCSCC patients. In AIM1, we seek to analyze young, low-risk OCSCC patients (cases) and traditional, high- risk patients (control) for epidemiologic risk factors and to perform integrated analysis of germline and somatic variants to further elucidate the genomic impact in OCSCC. We will then use high throughput RNASeq to analyze the transcriptome in these two groups to further characterize differences or similarities and allow greater insight into the potential mechanisms of tumorigenesis. In AIM2 we will investigate the impact of previously identified germline candidate gene mutations in the DNA repair and telomere maintenance pathways on tumorigenesis and genome instability using genetic editing and in vitro techniques. This study will allow us to develop and analyze data critical to understanding of OCSCC and to provide me, the P.I., the opportunity to develop the research tools, fund of knowledge, and skills necessary to perform this type of study as I seek to become an independently funded clinician-scientist. The P.I. is a head and neck surgical oncologist and witnesses the daily impact head and neck cancer has on patients, thus recognizes the need to improve patient care through translational research. The P.I. is an active member of the Head and Neck oncology program, who is strongly supported by his department, as well as a team of strong bio-informatics collaborators with significant experience in making substantial changes to the field of cancer genetics. The P.I. has designed a mentored training and educational program to directly correlate with the research aims to allow an integrated education for advanced sequencing techniques. Based on our joint experience, we expect our research to have high potential for translational application to patient care. In summary, this proposal has significant potential to dramatically impact the lives of patients with OCSCC and will provide substantial training and mentorship for the P.I. to become an independent investigator.

项目总结/摘要 口腔鳞状细胞癌（Oral cavity squamous cell carcinoma，OCSCC）是一种侵袭性和致命性疾病。虽然烟草 和酗酒是传统高危口腔鳞癌患者癌变的危险因素， 年轻患者的子集，即使在没有这些危险因素的情况下，也会发生散发性OCSCC。事业 年轻患者的OCSCC发病率仍不清楚，尽管他们年龄小且缺乏危险因素，但发病率仍很低。 生存根据我们的初步数据，似乎存在人口统计学、病因学和突变负担。 年轻、低风险（≤40岁，非吸烟者和非饮酒者）与传统、高风险之间的差异 （>50岁，>20包-年的烟草使用和高度饮酒）患者。我们正在寻求利用基因组 和转录组差异，以确定肿瘤发生的分子机制，重点是DNA 年轻、低风险OCSCC中的修复和端粒维持途径。 拟议的学习和培训目标是制定一项职业发展计划， 通过下一代测序进一步确定肿瘤发生的分子机制， 口腔鳞状细胞癌患者在AIM 1中，我们试图分析年轻的低风险OCSCC患者（病例）和传统的高风险OCSCC患者（病例）。 危险患者（对照）的流行病学危险因素，并进行生殖系和体细胞的综合分析， 进一步阐明OCSCC中的基因组影响。然后，我们将使用高通量RNASeq， 分析这两组中的转录组以进一步表征差异或相似性， 更深入地了解肿瘤发生的潜在机制。在AIM 2中，我们将研究 先前鉴定的DNA修复和端粒维持中的生殖系候选基因突变 使用基因编辑和体外技术研究肿瘤发生和基因组不稳定性的途径。本研究将 允许我们开发和分析对理解OCSCC至关重要的数据，并为我，PI，的 有机会开发研究工具，知识基金和执行此类研究所需的技能 因为我想成为一名独立资助的临床科学家私家侦探是一种头颈外科手术 肿瘤学家和证人的日常影响头部和颈部癌症对病人，因此认识到需要 通过转化研究改善患者护理。私家侦探是头颈部的活跃成员 肿瘤学计划，谁是他的部门的大力支持，以及强大的生物信息学团队 在癌症遗传学领域做出重大改变方面具有重要经验的合作者。私家侦探 设计了一个指导性的培训和教育计划，与研究目标直接相关， 先进测序技术的综合教育。根据我们的共同经验，我们希望 研究具有很高的潜力转化应用到病人护理。总而言之，该提案 显著的潜力，大大影响OCSCC患者的生活，并将提供大量的培训 和私人侦探的导师成为一名独立调查员