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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要口腔鳞状细胞癌（OCSCC）是一种侵袭性且致命的疾病，而烟草则是这种疾病。酗酒和酗酒是传统高危 OCSCC 患者致癌的危险因素，有即使没有这些危险因素，年轻患者的子集也会发展为散发性 OCSCC。年轻患者中 OCSCC 的发病率仍然未知，尽管他们年龄较小且缺乏危险因素，但其发病率仍很差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、不吸烟、不饮酒）与传统、高风险之间的差异（> 50 岁，> 20 年吸烟和酗酒）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 的修复和端粒维持途径。拟议的学习和培训目标是制定职业发展计划，这对于通过下一代测序进一步明确年轻人肿瘤发生的分子机制在 AIM1 中，我们试图分析年轻、低风险的 OCSCC 患者（病例）和传统的高风险 OCSCC 患者。风险患者（对照）的流行病学危险因素，并对种系和体细胞进行综合分析然后我们将使用高通量 RNASeq 来进一步阐明 OCSCC 中的基因组影响。分析这两组的转录组，以进一步表征差异或相似之处，并允许在 AIM2 中，我们将研究肿瘤发生的潜在机制。先前确定的 DNA 修复和端粒维持中的种系候选基因突变这项研究将利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。让我们能够开发和分析对于理解 OCSCC 至关重要的数据，并为我（P.I.）提供开发进行此类研究所需的研究工具、知识储备和技能的机会当我寻求成为一名独立资助的临床医生科学家时，P.I. 肿瘤学家并见证了头颈癌对患者的日常影响，因此认识到有必要 The P.I. 是 Head and Neck 的积极成员。肿瘤学项目，得到了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拥有丰富经验的合作者。设计了一个指导培训和教育计划，与研究目标直接相关，以便基于我们的共同经验，我们期望我们的先进测序技术的综合教育。研究在患者护理转化应用方面具有很高的潜力总之，该提案具有很大的潜力。显着影响 OCSCC 患者生活的巨大潜力，并将提供大量培训并指导 P.I. 成为一名独立调查员。