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: 8034838
• 负责人: QINGYI WEI
• 金额: $ 58.93万
• 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 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034838
• 关键词: Age; Alcohol consumption; Alleles; Benzo(a)pyrene; Biological Assay; Biological Markers; Cell physiology; Core Protein; DNA; DNA Repair; DNA Repair Gene; DNA repair protein; Data; Data Collection; Databases; Dimensions; ERCC1 gene; ERCC3 gene; Epidemiologic Studies; Epidemiology; Epoxy Compounds; Ethnic Origin; Ethnic group; Etiology; Evaluation; Family history of; Frequencies; Future; Gene Frequency; General Population; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genetic Transcription; Genome Stability; Genotype; Glycols; Goals; Haplotypes; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Health; In Vitro; Individual; Laryngeal Squamous Cell Carcinoma; Larynx; Lead; Lymphocyte; Malignant Neoplasms; Messenger RNA; Methods; Minor; Modeling; Molecular Epidemiology; Multivariate Analysis; National Institute of Environmental Health Sciences; Nature; Newly Diagnosed; Nucleotide Excision Repair; Oral cavity; Participant; Pathway interactions; Pharyngeal structure; Phase; Phenotype; Plasmids; Predisposition; Primary Prevention; Principal Component Analysis; Proteins; RNA; 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; base; computer based statistical methods; gene environment interaction; genetic variant; high throughput screening; instrument; mRNA Expression; mouth squamous cell carcinoma; protein expression; repository; sex; tumor

DESCRIPTION: Although smoking and alcohol use are major risk factors for squamous cell carcinoma of the head and neck (SCCHN), only a fraction of smokers develops SCCHN, suggesting a role for genetic susceptibility. We have found an association between increasing risk of SCCHN and suboptimal DNA repair capacity (DRC) that may be determined by adverse genetic variants such as single nucleotide polymorphisms (SNPs) in the nucleotide-excision repair (NER) genes. Therefore, we propose to focus in depth on the NER pathway by expanding from previously studied 5 non-synonymous SNPs (nsSNPs) to 85 common tagging SNPs (tSNPs) in the well-defined 8 core NER genes (i.e., ERCC1, XPA, XPB, XPC, XPD, XPE, XPF, and XPG), to correlate the variant alleles/genotypes or haplotypes/diplotypes with three NER phenotypes (i.e., NER mRNA expression, NER protein expression and NER DRC), and to evaluate their associations with risk of SCCHN. To accomplish these goals, we will include 1,600 SCCHN cases and 1,600 age-, sex-, and ethnicity-matched controls that consist of previously recruited 800 cases and 800 controls and an additional 800 cases and 800 controls to be recruited in this application using the same study design, selection criteria, and data collection instruments. To perform a comprehensive analysis of NER in SCCHN, our specific aims are: AIM 1: To determine the associations of the frequencies of variant alleles/haplotypes and genotypes/diplotypes of tSNPs in the 8 NER genes and the DRC phenotype with risk of SCCHN in 1,600 SCCHN cases and 1,600 controls. We will test the hypotheses that adverse alleles/haplotypes or genotypes/diplotypes of these selected genes and suboptimal DRC phenotype are associated with increased risk of SCCHN. AIM 2: To determine mRNA and protein expression levels of the 8 NER proteins by real-time RT-PCT assay and high-throughput reverse-phase protein lysate microarray assay, respectively, in cultured lymphocytes from 400 cases and 400 controls to be accrued. We will test the hypothesis that lower levels of NER mRNA and protein expression are associated with increased risk of SCCHN. AIM 3: To determine functional relevance of selected variant alleles and haplotypes of tSNPs of the 8 NER genes by correlating the frequencies of variant alleles/ haplotypes and genotypes/diplotypes with expression levels of mRNA and proteins of the 8 NER genes and DRC phenotype. This study will allow us to develop risk assessment models that integrate all biomarkers tested and epidemiological covariates. The relatively large sample size in this renewal allows for stratification analysis by tumor sites (i.e., oral cavity, pharynx and larynx), various genotypes/diplotypes and their combined genotypes, and epidemiologic covariates as well as for assessment of possible gene-gene and gene-environment interactions. This study will contribute to our understanding of the role of NER in the etiology of SCCHN and may lead to possible targets for primary prevention. PUBLIC HEALTH SIGNIFICANCE: This proposed study is to investigate the roles of genetic factors of DNA repair capacity (DRC), 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 preliminary findings to a role of DRC and its genetic determinants (85 single nucleotide polymorphisms, SNPs) in 8 DNA repair genes in a large study of 1600 cases and 1600 controls and applying our newly developed assays for mRNA and protein expression to 400 cases and 400 controls. Therefore, this study will help understand correlations between DRC genotypes (SNPs) and phenotypes (expression of mRNA and proteins and DRC) and their roles 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 of SCCHN in the general population.

产品说明：虽然吸烟和饮酒是头颈部鳞状细胞癌（SCCHN）的主要危险因素，但只有一小部分吸烟者会发生SCCHN，这表明遗传易感性的作用。我们发现SCCHN风险增加与次优DNA修复能力（DRC）之间存在关联，这可能是由不利的遗传变异如核苷酸切除修复（NER）基因中的单核苷酸多态性（SNP）决定的。因此，我们建议通过从先前研究的5个非同义SNP（nsSNP）扩展到明确定义的8个核心NER基因中的85个常见标签SNP（tSNP）来深入关注NER途径（即，ERCC 1、XPA、XPB、XPC、XPD、XPE、XPF和XPG），以将变体等位基因/基因型或单倍型/双倍型与三种NER表型（即，NER mRNA表达、NER蛋白表达和NER DRC），并评估其与SCCHN风险的相关性。为了实现这些目标，我们将纳入1，600例SCCHN病例和1，600例年龄、性别和种族匹配的对照，包括先前招募的800例病例和800例对照，以及本申请中使用相同的研究设计、选择标准和数据收集工具招募的另外800例病例和800例对照。为了对SCCHN中的NER进行全面分析，我们的具体目标是：目的1：在1，600例SCCHN病例和1，600例对照中确定8个NER基因中tSNP的变异等位基因/单倍型和基因型/双倍型的频率以及DRC表型与SCCHN风险的关系。我们将检验这些选定基因的不利等位基因/单倍型或基因型/双倍型和次优DRC表型与SCCHN风险增加相关的假设。目标2：分别采用实时荧光定量RT-PCT法和高通量蛋白芯片法检测400例患者和400例正常人培养淋巴细胞中8种NER蛋白的mRNA和蛋白表达水平。我们将检验较低水平的NER mRNA和蛋白表达与SCCHN风险增加相关的假设。目标3：通过将8个NER基因的tSNP的变异等位基因/单倍型和基因型/双倍型的频率与8个NER基因的mRNA和蛋白质的表达水平以及DRC表型相关联，确定8个NER基因的tSNP的选定变异等位基因和单倍型的功能相关性。这项研究将使我们能够开发风险评估模型，整合所有检测的生物标志物和流行病学协变量。本次更新中相对较大的样本量允许按肿瘤部位进行分层分析（即，口腔、咽和喉）、各种基因型/二倍体型和它们的组合基因型、流行病学协变量以及用于评估可能的基因-基因和基因-环境相互作用。这项研究将有助于我们理解NER在SCCHN病因学中的作用，并可能导致一级预防的可能目标。公共卫生意义：本研究旨在探讨DNA修复能力（DRC）的遗传因素及其与吸烟和饮酒的相互作用在口腔、咽和喉鳞状细胞癌（SCCHN）病因学中的作用，将我们的初步发现扩展到DRC及其遗传决定因素的作用（85个单核苷酸多态性，SNPs）在8个DNA修复基因的1600例和1600名对照的大型研究，并应用我们新开发的mRNA和蛋白质表达的测定400例和400名对照。因此，本研究将有助于了解DRC基因型（SNPs）和表型（mRNA和蛋白质的表达和DRC）之间的相关性及其在SCCHN病因学中的作用。本研究的长期目标是确定有效的生物标志物，可用于识别在一般人群中作为SCCHN一级预防目标的高危个体。