MOLECULAR EPIDEMIOLOGY OF HEAD AND NECK CANCER

头颈癌的分子流行病学

• 批准号: 7608293
• 负责人: RADOSLAV GOLDMAN
• 金额: $ 0.22万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7608293
• 关键词: Age; Alcohol consumption; Apoptosis; Apoptotic; Base Excision Repairs; Bleomycin; Blood specimen; Bread; Cancer Control; Cancer Etiology; Case-Control Studies; Cells; Clinical Data; Comet Assay; Computer Retrieval of Information on Scientific Projects Database; DNA; DNA Damage; DNA Repair; DNA Repair Gene; Data; ERCC2 gene; Frequencies; Funding; Gender; Gene Mutation; Genetic; Genetic Predisposition to Disease; Genotoxic Stress; Goals; Grant; Head and Neck Cancer; Head and Neck Neoplasms; Human; Individual; Institution; Leukocytes; Lymphocyte; Malignant Neoplasms; Measures; Molecular Epidemiology; Mutagens; Mutate; Mutation; Nucleotide Excision Repair; Pathway interactions; Pilot Projects; Predisposition; Prevention strategy; Protein p53; Race; Rate; Research; Research Design; Research Personnel; Resources; Risk; Risk Factors; Saliva; Smoking; Smoking Status; Source; Specimen; TP53 gene; Tail; Testing; Tissues; Tumor Suppressor Genes; Tumor Tissue; United States National Institutes of Health; Urine; XRCC1 gene; XRCC3 gene; cancer prevention; cancer risk; design; genetic variant; head and neck cancer prevention; human APEX1 protein; recombinational repair; repaired; repository; response; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background: Smoking and alcohol consumption are the dominant risk factors for head and neck (HN) cancer but little is known about the genetic factors defining individual susceptibility. This study is designed to search for risk factors among phenotypic and genotypic markers of response to genotoxic stress. Comet assay and mutagen sensitivity evaluate response to DNA damage (e.g. bleomycin exposure) in short-term cultured human lymphocytes. Mutagen sensitivity was previously used as a marker of HN cancer risk and comet assay is an increasingly popular measure of DNA damage and repair that has yet to be tested in HN cancer. High DNA damage (tail moment in comet assay or chromaid breads in mutagen sensitivity) and low rate of DNA repair correlate with increased risk of certain cancers. This study will evaluate comet assay as a measure of HN cancer risk. Programed cell death (apoptosis) is one way to eliminate cells that did not repair correctly DNA damage. We hypothesize that low apoptotic response to bleomycin exposure in the short-term cultured lymphocytes is indicative of increased cancer risk. In addition we will examine how these phenotypic measures in white blood cells correlate with mutations of the p53 tumor suppressor gene in the tumor issue. The p53 gene guards cells from carcinogenic changes and is often mutated in HN cancer. It is expected that insufficient response to genotoxic stress correlates with high frequency of some p53 mutations. Genetic variants with decreased DNA repair capacity were previously described in both base excision repair (APE1, XRCC1), nucleotide excision repair (XPD), and recombinational repair (XRCC3) pathways. Correlation of these genetic variants with DNA damage/repair (comet assay), apoptosis, and p53 mutations in HN tumor tissue will be examined. Hypothesis: Our hypothesis is that head and neck cancer risk is related to inter individual variability in the response to genotoxic stress. Specific Aims: This study has two major goals. Aim 1 - Establish a data and tissue repository for studies of HN cancer. Aim2 - Use the repository to determine whether decreased ability to respond to DNA damage correlates with increased HN cancer risk. Study Design: The case-control study will evaluate 100 HN cancer cases and 100 non-cancer controls matched on age, gender, race and smoking status. Epidemiological data, clinical data, and samples of blood, buccal cells, saliva, urine, and tumor tissue will be obtained and examined for markers of genetic susceptibility to HN cancer. White blood cells will be cultured for a short term to test response to DNA damage (comet assay, mutagen sensitivity and apoptosis) and DNA and other biomolecules will be extracted from the various specimen to evaluate genetic variants in DNA repair genes, mutations in the p53 tumor suppressor gens, and other markers of cancer susceptibility. Significance: This pilot study is expected to fill important gaps in our understanding of HN cancer etiology, identify genetic modifiers of HN cancer risk, produce new hypotheses to focus HN cancer prevention, and help design better cancer prevention strategies.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 背景：吸烟和饮酒是头颈部（HN）癌症的主要危险因素，但对定义个体易感性的遗传因素知之甚少。这项研究旨在寻找对遗传毒性应激的反应的表型和基因型标记中的危险因素。彗星测定和诱变剂敏感性评估了短期培养的人淋巴细胞中对DNA损伤的反应（例如博来霉素暴露）。诱变剂的敏感性先前被用作HN癌症风险的标志，彗星测定是越来越流行的DNA损伤和修复方法，尚未在HN癌症中进行测试。高DNA损伤（彗星测定中的尾矩或诱变剂敏感性中的铬铁面包）和DNA修复率低与某些癌症的风险增加相关。 这项研究将评估彗星测定法作为HN癌症风险的量度。编程的细胞死亡（凋亡）是消除未正确修复DNA损伤的细胞的一种方法。我们假设在短期培养的淋巴细胞中对博来霉素暴露的凋亡反应低表明癌症风险增加。此外，我们将研究白细胞中的这些表型测量与肿瘤问题中p53肿瘤抑制基因的突变如何相关。 p53基因从致癌的变化中理固定细胞，通常在HN癌中突变。预计对遗传毒性应激的反应不足与某些p53突变的高频相关。先前在碱基切除修复（APE1，XRCC1），核苷酸切除修复（XPD）和重组修复（XRCC3）途径中都描述了具有DNA修复能力降低的遗传变异。这些遗传变异与DNA损伤/修复（彗星测定），凋亡和p53突变的相关性将被检查。 假设：我们的假设是头颈癌的风险与对遗传毒性应激的反应中的个体变异性有关。 具体目的：这项研究有两个主要目标。目标1-建立一个数据和组织存储库，以进行HN癌的研究。 AIM2-使用存储库来确定降低对DNA损伤的能力是否与HN癌症风险增加相关。 研究设计：病例对照研究将评估100例HN癌症病例和100个与年龄，性别，种族和吸烟状况相匹配的非癌症对照。将获得并检查流行病学数据，临床数据以及血液，颊细胞，唾液，尿液和肿瘤组织的样本，并检查是否有遗传易感性HN癌易感性的标记。白细胞将在短期内进行培养，以测试对DNA损伤的反应（彗星测定，诱变剂敏感性和凋亡），DNA和其他生物分子将从各种样品中提取，以评估DNA修复基因中的遗传变异，在p53肿瘤抑制p53肿瘤的突变中，抑制p53肿瘤的抑制剂抑制剂和其他标记物的标记和其他癌症的癌症。 意义：这项试点研究有望填补我们对HN癌症病因的理解，确定HN癌症风险的遗传修饰剂，产生新的假设，以预防HN癌症，并帮助设计更好的预防癌症预防策略。