P-1: Intrinsic Apoptosis Phenotype and Susceptibility to Squamous Cell Carcinoma

P-1：内在凋亡表型和鳞状细胞癌的易感性

• 批准号: 7510668
• 负责人: QINGYI WEI
• 金额: $ 16.95万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7510668
• 关键词: Age; Alcohol consumption; Antigens; Apoptosis; Apoptosis Promoter; Apoptotic; BAK1 gene; BAX gene; Bax protein; Biological Assay; Biological Markers; CASP9 gene; CDKN1A gene; Camptothecin; Cell Death; Cells; Collaborations; Correlation Studies; County; DNA Damage; DNA Repair; Data; Databases; Early Diagnosis; Environment; Epithelial Cells; Ethnic Origin; Etiology; Frequencies; Future; Gene Frequency; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genotype; Goals; Head and Neck Cancer; Hospitals; Individual; International; Lead; Lymphocyte; MDM2 gene; MDM2 gene; Measures; Mediating; Minor; Mitochondria; Molecular Epidemiology; Mutation; Newly Diagnosed; Pathway interactions; Peripheral; Phenotype; Play; Predisposition; Primary Prevention; Publishing; Race; Recruitment Activity; Reproduction spores; Research; Resources; Risk; Risk Assessment; Risk Factors; Role; Sampling; Single Nucleotide Polymorphism; Smoke; Smoker; Smoking; Squamous cell carcinoma; TP53 gene; Testing; Tobacco use; Tobacco-Associated Carcinogen; Topoisomerase-I Inhibitor; Validation; Variant; Work; bak protein; base; cancer epidemiology; cancer risk; carcinogenesis; case control; caspase-3; epidemiology study; genetic variant; interest; malignant mouth neoplasm; mouth squamous cell carcinoma; novel; oncoprotein p21; repaired; residence; response; sex

Only a fraction of smokers and drinkers develop SCCOC, suggesting that genetic susceptibility plays a role in the etiology of SCCOC. Our previous studies have established that host-cell DNA repair capacity and related genetic variations, as measured by polymorphisms, are susceptibility factors for SCCOC. To date, no published studies have investigated apoptotic capacity as a susceptibility factor for SCCOC. There are at least two known apoptotic pathways, intrinsic and extrinsic, that lead to cell death. While the extrinsic pathway of apoptosis is primarily important in the immunological mechanisms of antigen-induced cell death, the intrinsic or mitochondrial pathway of apoptosis is activated in response to unrepaired DNA damage. Therefore, we hypothesize that genetically determined capacity of the intrinsic apoptotic pathway is associated with risk of SCCOC. In this new proposal, we have the following specific aims: Aim 1: To establish a comprehensive database for 600 prospectively accrued (including 300 recruited in the previous SPORE project), newly diagnosed SCCOC cases and 600 hospital-based and genetically unrelated controls (including 300 recruited in an R01-supported project), frequency-matched by age, sex, ethnicity/race and county of residence; Aim 2: To determine differences in phenotypes of the established intrinsic apoptosis capacity between 300 cases and 300 controls. We will test the hypothesis that CPTinduced apoptotic capacity is lower in SCCOC cases than in controls and is modified by known risk factors such as smoking and alcohol use; Aim 3: To determine the associations between variant apoptotic genotypes and risk of SCCOC in the 600 cases and 600 controls that will have genotyping data for the case-control analysis, which will generate new hypotheses for further validation by future larger studies and the INHANCE group; and Aim 4: To study the correlations between apoptotic phenotypes and functional polymorphisms (genetic variants) in 300 cases and 300 controls. We will test the hypothesis that intrinsic apoptotic capacity is correlated with (predicted by) common functional genetic variants of selected apoptotic genes in 300 cases and 300 controls that will have apoptotic phenotype data. This proposed study is highly hypothesis-driven and expands on our previous work and preliminary data from a novel p53-PHB-PIG3 apoptosis mechanism (see Preliminary Data). Our long-term goal is to identify effective biomarkers for risk assessment and at-risk individuals who can be targeted for primary prevention and early detection of SCCOC. Future studies to test the biomarkers developed through this application may be brought forward through the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, a collaboration of research groups leading large molecular epidemiology studies of head & neck cancer that includes the participation of the Project Leader, Dr. Wei, and Co-Leader, Dr. Sturgis.

只有一小部分吸烟者和饮酒者会患上SCCOC，这表明遗传易感性在其中发挥了作用。 SCCOC的病因学。我们以前的研究已经证实，宿主细胞的DNA修复能力和 通过多态性测量的相关遗传变异是SCCOC的易感因素。到目前为止， 还没有发表的研究将凋亡能力作为SCCOC的易感性因素进行研究。有 至少两种已知的导致细胞死亡的内源性和外源性凋亡途径。虽然外在的 细胞凋亡途径在抗原诱导的细胞免疫机制中起重要作用 死亡，细胞凋亡的内在或线粒体途径被激活，以响应未修复的DNA 损害因此，我们假设，遗传决定的内在凋亡途径的能力， 与SCCOC的风险有关。在这项新建议中，我们有以下具体目标：目标1： 为600名预期应计人员建立一个全面的数据库（包括前一年征聘的300名 SPORE项目），新诊断的SCCOC病例和600例基于医院和遗传无关的 对照组（包括在R 01支持的项目中招募的300人），按年龄，性别， 目的2：确定已建立的表型差异， 300例患者与300例对照者的内在凋亡能力之间的差异。我们将检验CPT诱导的 SCCOC病例的凋亡能力低于对照组，并受已知风险的影响 吸烟和饮酒等因素;目标3：确定变量之间的关联 600例病例和600例对照中的细胞凋亡基因型和SCCOC风险，将有基因分型数据 病例对照分析，这将产生新的假设，进一步验证未来更大的 目的4：研究凋亡表型和INHANCE组之间的相关性， 300例病例和300例对照的功能多态性（遗传变异）。我们将检验这个假设， 内在的凋亡能力与常见的功能性遗传变异相关（由其预测）， 在300例病例和300例对照中选择凋亡基因，这些基因将具有凋亡表型数据。这 拟议的研究是高度假设驱动的，并扩大了我们以前的工作和初步数据，从 一种新的p53-PHB-PIG 3凋亡机制（见初步数据）。我们的长期目标是确定 用于风险评估的有效生物标志物和可作为一级预防目标的高危个体 早期发现SCCOC。未来的研究将测试通过该应用开发的生物标志物 可以通过国际头颈癌流行病学（INHANCE）提出 联合会，一个研究小组的合作，领导大型分子流行病学研究的头部和 颈部癌症，包括项目负责人魏博士和共同负责人Sturgis博士的参与。