Genotypes and Phenotypes of Apoptosis and Risk of Head and Neck Cancer

细胞凋亡的基因型和表型以及头颈癌的风险

• 批准号: 7778901
• 负责人: QINGYI WEI
• 金额: $ 63.4万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-02 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7778901
• 关键词: ATM gene; Age; Alcohol consumption; Apoptosis; Apoptosis Promoter; Apoptotic; Applications Grants; BAX gene; BCL2 gene; BRCA1 gene; Biological Assay; Biological Markers; CASP10 gene; CASP8 gene; CDK6-associated protein p18; Camptothecin; Cell Culture Techniques; Cell Cycle Checkpoint; Cell Cycle Regulation; Cell Death; Cells; Correlation Studies; DNA; DNA Damage; DNA Repair; DNA-Protein Interaction; Data; E2F1 gene; Early Diagnosis; Epidemiology; Ethnic Origin; Etiology; Flow Cytometry; Frequencies; Gene Frequency; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Goals; Haplotypes; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Hospitals; Human Papillomavirus; Individual; Infection; International; Knowledge; Laboratories; Laryngeal Squamous Cell Carcinoma; Lead; Lymphocyte; MDM2 gene; Malignant Neoplasms; Measures; Mediating; Methodology; Methods; Minor; Mutation; Newly Diagnosed; Pathway interactions; Patients; Peripheral; Peripheral Blood Lymphocyte; Pharyngeal structure; Phenotype; Play; Population Study; Predisposition; Primary Prevention; Publishing; Questionnaires; RB1 gene; Race; Recruitment Activity; Regulation; Reporting; Risk; Risk Assessment; Risk Factors; Role; Sample Size; Sampling; Single Nucleotide Polymorphism; Smoke; Smoker; Smoking History; Squamous cell carcinoma; Statistical Models; Stratification; Subgroup; TNFRSF10A gene; TNFRSF10B gene; TP53 gene; Testing; Tobacco; Tobacco-Associated Carcinogen; Topoisomerase-I Inhibitor; Variant; base; burden of illness; cancer epidemiology; cancer risk; caspase-3; disorder prevention; gene environment interaction; gene interaction; genetic variant; mouth squamous cell carcinoma; novel; public health relevance; residence; response; sex; uncontrolled cell growth

DESCRIPTION (provided by applicant): Tobacco and alcohol use and genetic susceptibility are major risk factors for squamous cell carcinoma of the head and neck (SCCHN). Identification of susceptible individuals can effectively facilitate prevention of this disease by avoiding tobacco and alcohol use. Tobacco carcinogens cause a variety of DNA damage in the target cells, which may lead to uncontrolled cell growth, but the cells evolve to have the mechanism of programmed cell death (apoptosis), which helps eliminate cells with excessive DNA damage and thus reduce cancer risk. At least two known apoptotic pathways, the intrinsic and extrinsic, lead to cell death in response to excessive DNA damage, and there is an established flow-cytometry method to detect the apoptosis phenotype. In this new grant application, we propose to perform apoptosis phenotyping and genotyping assays in 600 newly recruited patients with SCCHN and 600 control subjects and to perform genotyping assays for an additional 1,000 SCCHN patients and 1,000 control subjects with stored DNA samples procured previously. A total of 434 common (including 88 putatively functional and 346 tagging) SNPs of 50 apoptosis-related genes have been selected and will be genotyped by using the SNPlex genotyping method for all 3,200 subjects (1,600 cases and 1,600 controls). Our specific aims are: AIM 1: To determine the association between 434 common SNPs (i.e., minor allele frequency e 0.05) genotypes of 50 selected apoptosis-related genes and the risk of SCCHN. We will also detect TP53 mutations and HPV infection of a subset of 480 SCCHN patients to be prospectively recruited, aiming at identifying the most susceptible subgroups in this study population. AIM 2: To determine the association between the apoptotic phenotype and the risk of SCCHN. AIM 3: To determine the functional relevance of selected common tagging SNPs in apoptotic pathways by identifying the genotypes that predict the phenotypes. We will also explore the gene-gene and gene-environment interactions using the genotyping data from all 1,600 cases and 1,600 controls and questionnaire data that characterized the smoking history of each individual and identify the most susceptible subgroups in this study population. This proposed association study is highly hypothesis driven, expanding our preliminary data on the findings of a novel p53-PHB-PIG3 apoptosis mechanism. This study will identify genetic factors that predict the apoptotic phenotype and risk of SCCHN and thus will advance our knowledge of the etiology of SCCHN. The long-term goal of this study is to identify effective biomarkers for risk assessment and to identify at-risk individuals who can be targeted for primary prevention and early detection of SCCHN in the general population. PUBLIC HEALTH RELEVANCE: The purpose of this proposed study is to investigate the roles of genetic factors, as well as their interactions with tobacco and alcohol use as well as p53 mutations and HPV infections, in the etiology of squamous cell carcinomas of the oral cavity, pharynx, and larynx (SCCHN), expanding our findings of a novel apoptosis mechanism that has not been described before. Therefore, this study will help us understand the underlying mechanisms of the correlation between apoptosis genotypes and phenotypes to be measured and the roles they may play in the etiology of SCCHN. The long-term goal of this study is to identify effective biomarkers that can be used to identify at-risk individuals in the general population who will be targeted for primary prevention and early detection of SCCHN.

描述（由申请人提供）：吸烟、饮酒和遗传易感性是头颈部鳞状细胞癌（SCCHN）的主要危险因素。确定易感个体可以通过避免使用烟草和酒精有效地促进预防这种疾病。烟草致癌物在靶细胞中引起多种DNA损伤，可能导致细胞生长失控，但细胞进化出细胞程序性死亡（凋亡）机制，有助于消除DNA损伤过度的细胞，从而降低癌症风险。至少有两种已知的凋亡途径，内在的和外在的，导致细胞死亡，以应对过度的DNA损伤，并且有一种成熟的流式细胞术方法来检测细胞凋亡表型。在这项新的资助申请中，我们建议对600名新招募的SCCHN患者和600名对照受试者进行细胞凋亡表型和基因分型分析，并对另外1000名SCCHN患者和1000名对照受试者进行基因分型分析，这些患者使用之前获得的存储DNA样本。总共选择了50个凋亡相关基因的434个共同snp（包括88个推定功能snp和346个标记snp），并将对所有3200名受试者（1600例病例和1600例对照）使用SNPlex基因分型方法进行基因分型。我们的具体目标是：目的1：确定50个选定的凋亡相关基因的434个常见snp（即小等位基因频率0.05）基因型与SCCHN风险之间的关系。我们还将检测480名SCCHN患者的TP53突变和HPV感染，以确定该研究人群中最易感的亚群。目的2：确定细胞凋亡表型与SCCHN风险之间的关系。目的3：通过鉴定预测表型的基因型，确定凋亡途径中选定的常见标记snp的功能相关性。我们还将利用来自所有1600例病例和1600例对照的基因分型数据以及描述每个个体吸烟史的问卷数据来探索基因-基因和基因-环境相互作用，并确定本研究人群中最易感的亚群。这项拟议的关联研究是高度假设驱动的，扩展了我们关于p53-PHB-PIG3新凋亡机制的初步数据。本研究将确定预测SCCHN凋亡表型和风险的遗传因素，从而提高我们对SCCHN病因学的认识。本研究的长期目标是确定用于风险评估的有效生物标志物，并确定在普通人群中可以针对初级预防和早期发现SCCHN的高危个体。公共卫生相关性：本研究的目的是研究遗传因素的作用，以及它们与烟草和酒精使用以及p53突变和HPV感染的相互作用，在口腔、咽和喉部鳞状细胞癌（SCCHN）的病因学中，扩展我们对以前未描述的新的细胞凋亡机制的发现。因此，本研究将有助于我们了解细胞凋亡基因型与待测表型之间相关的潜在机制，以及它们在SCCHN病因学中可能发挥的作用。本研究的长期目标是确定有效的生物标志物，可用于识别普通人群中的高危个体，这些个体将成为初级预防和早期发现SCCHN的目标。