Molecular Epidemiology of DNA Repair in Head and Neck Cancer

头颈癌 DNA 修复的分子流行病学

• 批准号: 8231996
• 负责人: QINGYI WEI
• 金额: $ 51.34万
• 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: 2008-03-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231996
• 关键词: Age; Alcohol consumption; Alleles; Amino Acids; Apoptosis; Apoptotic; Applications Grants; Benzo(a)pyrene; Biological Assay; Biological Markers; Cell Death; Cell physiology; Cells; Core Protein; DNA; DNA Damage; DNA Repair; DNA Repair Gene; Data; Data Collection; Databases; Dimensions; Disease; ERCC1 gene; ERCC3 gene; Early Diagnosis; Epidemiologic Studies; Epidemiology; Epoxy Compounds; Ethnic Origin; Ethnic group; Etiology; Evaluation; Family history of; Flow Cytometry; Frequencies; Future; Gene Expression; Gene Frequency; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genome Stability; Genomics; Genotype; Glycols; Goals; Haplotypes; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Hospitals; In Vitro; Individual; Knowledge; Laryngeal Squamous Cell Carcinoma; Larynx; Lead; Lymphocyte; Malignant Neoplasms; Measures; Messenger RNA; Methods; Minor; Modeling; Molecular Epidemiology; Multivariate Analysis; National Institute of Environmental Health Sciences; Nature; Newly Diagnosed; Nucleic Acid Regulatory Sequences; Nucleotide Excision Repair; Oral cavity; Participant; Pathway interactions; Pharyngeal structure; Phase; Phenotype; Plasmids; Play; Predisposition; Primary Prevention; Principal Component Analysis; Proteins; RNA; Race; Recruitment Activity; Research Design; Resources; Risk; Risk Assessment; Risk Factors; Role; Sample Size; Sampling; Selection Criteria; Single Nucleotide Polymorphism; Site; Smoker; Smoking; Specimen; Statistical Models; Stratification; Subgroup; Testing; Time; Tobacco use; Tobacco-Associated Carcinogen; Transfection; Validation; Variant; XPA gene; abstracting; base; cancer risk; computer based statistical methods; gene environment interaction; genetic variant; high throughput screening; instrument; mRNA Expression; mouth squamous cell carcinoma; novel; prevent; prospective; protein expression; repository; residence; response; sex; tumor; uncontrolled cell growth

Project Summary/Abstract 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 prevent 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 or apoptosis that helps eliminate cells with excessive damage to DNA and thus reduce risk of cancer. There are at least two known apoptotic pathways, intrinsic and extrinsic, that lead to cell death in response to excessive DNA damage. Many genes participate in these two apoptotic pathways, and there is an established flow cytometry method to detect the apoptosis phenotype. In this new grant application, we propose to perform the phenotypic apoptosis and genotyping assays in 600 newly recruited cases and 600 controls and to perform genotyping assays with stored DNA samples from previously recruited 1,000 SCCHN cases and 1,000 controls. For the genotyping, we propose to focus on the common, possibly functional single nucleotide polymorphisms (SNPs) that either cause amino acid changes or sequence variation in the regulatory regions that may alter gene expression or are reportedly associated with risk of smoking-related cancers. A total of 88 possibly functional SNPs in 45 apoptosis-related genes will be genotyped by the Taqman genotyping method using genomic DNA from 1,600 SCCHN cases (600 prospective and 1,000 retrospective) and 1,600 cancer- free controls (also 600 prospective and 1,000 retrospective). Our specific aims are: AIM 1: To determine the association between the apoptotic phenotype of lymphocytes and risk of SCCHN in 600 prospectively identified cases and 600 hospital-based controls frequency matched by age, sex, ethnicity/race and residence. We will test the hypothesis that lower levels of apoptotic capacity are associated with increased risk of SCCHN. AIM 2: To determine the functional relevance of selected common variants in apoptotic pathways in the 600 cases and 600 controls by identifying genotypes that predict the phenotype. We will test the hypothesis that possibly functional genetic variants of selected apoptotic genes have an effect on the apoptotic phenotype. AIM 3: To determine the association between common variant genotypes of the selected apoptosis-related genes and risk of SCCHN. We will test the hypothesis that adverse genotypes of selected apoptosis-related genes are associated with increased risk of SCCHN. 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 in 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. Project Narrative This proposed study is to investigate the roles of genetic factors, as well as their interactions with tobacco and alcohol use, 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 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 who will be targeted for primary prevention and early detection of SCCHN in the general population.

项目概要/摘要 吸烟和饮酒以及遗传易感性是鳞状细胞癌的主要危险因素 头部和颈部 (SCCHN)。识别易感人群可有效预防该病 避免吸烟和饮酒。烟草致癌物对靶细胞造成多种DNA损伤， 这可能会导致细胞生长不受控制，但细胞进化到具有程序化细胞的机制 死亡或细胞凋亡有助于消除 DNA 过度损伤的细胞，从而降低患癌症的风险。 至少有两种已知的细胞凋亡途径，内在的和外在的，导致细胞死亡 过度的DNA损伤。许多基因参与这两种细胞凋亡途径，并且有一个已确定的 流式细胞术方法检测细胞凋亡表型。在这个新的拨款申请中，我们建议执行 对 600 个新招募的病例和 600 个对照进行表型凋亡和基因分型测定，并进行 使用先前招募的 1,000 个 SCCHN 病例和 1,000 个病例中储存的 DNA 样本进行基因分型测定 控制。对于基因分型，我们建议重点关注常见的、可能有功能的单核苷酸 多态性 (SNP) 会导致调节区域的氨基酸变化或序列变异 这可能会改变基因表达或据报道与吸烟相关癌症的风险有关。共88个 45个凋亡相关基因中可能有功能的SNP将通过Taqman基因分型方法进行基因分型 使用来自 1,600 个 SCCHN 病例（600 个前瞻性病例和 1,000 个回顾性病例）和 1,600 个癌症病例的基因组 DNA 自由控制（还有 600 个前瞻性和 1,000 个回顾性）。我们的具体目标是： 目标 1：确定 600 例前瞻性鉴定的淋巴细胞凋亡表型与 SCCHN 风险之间的关联 病例和 600 个医院对照频率按年龄、性别、民族/种族和居住地进行匹配。我们将 检验较低水平的细胞凋亡能力与 SCCHN 风险增加相关的假设。 目标 2：确定 600 种细胞凋亡途径中选定的常见变异的功能相关性 通过识别预测表型的基因型，对病例和 600 个对照进行研究。我们将检验以下假设： 选定的凋亡基因的可能功能性遗传变异对凋亡有影响 表型。目标 3：确定所选样本的常见变异基因型之间的关联 凋亡相关基因和 SCCHN 风险。我们将检验以下假设：所选的不良基因型 凋亡相关基因与 SCCHN 风险增加相关。这项拟议的关联研究是 高度假设驱动，扩展了我们关于新型 p53-PHB-PIG3 凋亡发现的初步数据 机制。这项研究将确定预测细胞凋亡表型和 SCCHN 风险的遗传因素和 这将增进我们对 SCCHN 病因学的了解。这项研究的长期目标是确定 用于风险评估和识别可作为初级治疗目标的高危个体的有效生物标志物 普通人群中 SCCHN 的预防和早期发现。项目叙述 这项拟议的研究旨在调查遗传因素的作用以及它们与 吸烟和饮酒是口腔、咽和喉鳞状细胞癌的病因 （SCCHN），扩展了我们对以前从未描述过的新型细胞凋亡机制的发现。 因此，本研究将有助于理解细胞凋亡之间相关性的潜在机制。 待测量的基因型和表型以及它们在 SCCHN 病因学中可能发挥的作用。长- 本研究的长期目标是确定有效的生物标志物，可用于识别高危个体 成为普通人群 SCCHN 一级预防和早期检测的目标。