RISK ASSESSMENT OF DNA REPAIR HETEROGENEITY IN HUMANS

人类 DNA 修复异质性的风险评估

• 批准号: 2634340
• 负责人: Bennett Van Houten
• 金额: $ 21.76万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2634340
• 关键词: DNA damage; DNA repair; basal cell carcinoma; biomarker; cancer risk; cell death; clone cells; cytotoxic T lymphocyte; gene expression; gene frequency; gene mutation; human subject; hypoxanthine phosphoribosyltransferase; interview; luciferin monooxygenase; neoplasm /cancer genetics; polymerase chain reaction; questionnaires; radiation genetics; radiation related neoplasm /cancer; reporter genes; squamous cell carcinoma; statistics /biometry; ultraviolet radiation

The ubiquitous environmental gentoxicant, ultraviolet light (UV), produces DNA damage, which if left unrepaired, can give rise to several biological effects including cell death, mutations and cancer. The human disease, xeroderma pigmentosum, exemplifies how reduced DNA repair capacity can lead to a higher incidence of cell lethality, higher mutation frequencies and a predisposition to cancer. The repair of UV-induced DNA damage is achieved by a complex interaction of >10 different gene products in a process called nucleotide excision repair. There is increasing evidence that DNA repair capacity, like any phenotypic trait, is heterogeneously distributed among the human population. Therefore certain individuals within the human population with low DNA repair capacity may be more prone to the adverse biological effects of environmental genotoxic agents, such as UV light. The goal of this study is to validate and apply within the human population several biomarkers of exposure and susceptibility to the environmental mutagen, ultraviolet light. In order to achieve this goal we will examine DNA repair capacity, cytotoxicity, and mutation frequency in peripheral lymphocytes of patients with skin cancer. More specifically the patient cohorts will be defined by the presence of one or more basal cell or squamous cell carcinomas and will be stratified into three age groups: l) less than 40 years old, 2) 40-50 years old, and 3) greater than 50 years old. Two major age-independent subgroups will be those patients with multiple skin cancers (MSC), (6 or greater) and patients with site clustering of skin cancers at specific body surfaces. All patients will be paired to age/sex-matched controls. We will test the hypothesis that low DNA repair capacity and high in vivo mutant frequency will correlate with increased risk of skin cancer using two DNA repair assays (SA1&2), a cytotoxicity assay (SA3) and an assay which measures the in vivo mutant frequency in a somatic gene (hypoxanthine phosphoribosyl transferase, HPRT) (SA4). Finally, in vitro studies of repair in isolated mutant clones will define the intra-individual interclonal heterogeneity of susceptibility to UV damage (SA6). The long-term goal of this study is to better understand the role of DNA repair in cancer susceptibility.

无处不在的环境基因毒物，紫外线（UV），产生 DNA损伤，如果不修复，可以引起几种生物学上的疾病。 影响包括细胞死亡、突变和癌症。人类的疾病， 着色性干皮病，证实了DNA修复能力的降低如何 导致更高的细胞致死率、更高的突变频率 和患癌症的倾向紫外线诱导的DNA损伤的修复是 通过在一个基因组中>10种不同基因产物的复杂相互作用实现。 这个过程叫做核苷酸切除修复。越来越多的证据 DNA修复能力，像任何表型特征一样， 分布在人类中。因此，某些人 在DNA修复能力低的人群中， 环境遗传毒性剂的不良生物效应， 像紫外线一样。本研究的目的是验证和应用在 人群暴露和易感性的几种生物标志物 环境诱变剂紫外线为了实现这一目标，我们 将检查DNA修复能力，细胞毒性和突变频率， 皮肤癌患者的外周血淋巴细胞。更具体地 患者群组将通过一个或多个基底细胞的存在来定义 或鳞状细胞癌，并将分为三个年龄组： l）40岁以下，2）40-50岁，3）50岁以上 岁两个主要的年龄无关亚组将是以下患者： 多发性皮肤癌（MSC），（6个或更多）和患者的部位 皮肤癌在特定身体表面的聚集。所有患者将被 与年龄/性别匹配的对照组配对。我们将检验一个假设， DNA修复能力和体内高突变频率将与 使用两种DNA修复试验（SA1&2）， 细胞毒性测定（SA 3）和测量体内突变体的测定 体细胞基因中的频率（次黄嘌呤磷酸核糖基转移酶， HPRT）（SA4）。最后，在离体研究中， 将定义个体内克隆间异质性， 对紫外线损伤的敏感性（SA 6）。这项研究的长期目标是 更好地理解DNA修复在癌症易感性中的作用。