MOLECULAR EPIDEMIOLOGY OF HEAD AND NECK CANCER

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 背景：吸烟和饮酒是头颈部(HN)癌症的主要危险因素，但对决定个体易感性的遗传因素知之甚少。本研究旨在寻找遗传毒性应激反应的表型和遗传型标志物中的危险因素。彗星试验和诱变剂敏感性评估短期培养的人淋巴细胞对DNA损伤(例如，博莱霉素暴露)的反应。诱变剂敏感性以前被用作HN癌症风险的标志，彗星试验是一种越来越受欢迎的DNA损伤和修复指标，但尚未在HN癌症中进行测试。较高的DNA损伤(彗星试验中的尾部时刻或突变敏感度中的ChromaID面包)和较低的DNA修复率与某些癌症的风险增加相关。这项研究将评估彗星试验作为衡量HN癌症风险的方法。程序性细胞死亡(细胞凋亡)是消除没有正确修复DNA损伤的细胞的一种方法。我们假设短期培养的淋巴细胞对博莱霉素的低凋亡反应预示着癌症风险的增加。此外，我们还将研究白细胞中的这些表型指标如何与肿瘤问题中的p53肿瘤抑制基因突变相关。P53基因保护细胞免受致癌变化，在HN癌中经常发生突变。预计对遗传毒性应激反应不足与某些P53突变的高频率相关。DNA修复能力下降的遗传变异以前在碱基切除修复(APE1，XRCC1)、核苷酸切除修复(XPD)和重组修复(XRCC3)途径中被描述。这些遗传变异与DNA损伤/修复(彗星试验)、细胞凋亡和HN肿瘤组织中P53突变的相关性将被检测。 假设：我们的假设是，头颈部癌症的风险与个体对基因毒性应激反应的差异性有关。 具体目标：这项研究有两个主要目标。目的1-建立HN癌研究的数据和组织信息库。AIM2-使用资料库来确定对DNA损伤的反应能力降低是否与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例按年龄、性别、种族和吸烟状况匹配的非癌症对照病例。将获得流行病学数据、临床数据以及血液、口腔细胞、唾液、尿液和肿瘤组织的样本，并检查HN癌的遗传易感性标记。白细胞将被短期培养，以测试对DNA损伤的反应(彗星试验、诱变剂敏感性和细胞凋亡)，并将从各种样本中提取DNA和其他生物分子，以评估DNA修复基因的遗传变异、p53肿瘤抑制基因的突变，以及其他癌症易感性标记。 意义：这项先导性研究有望填补我们对HN癌症病因学理解的重要空白，确定HN癌症风险的基因修饰因素，提出专注于HN癌症预防的新假设，并帮助设计更好的癌症预防策略。

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.