RISK ASSESSMENT OF DNA REPAIR HETEROGENEITY IN HUMANS

这种无处不在的环境赤毒剂，紫外线(UV)，会产生 DNA损伤，如果不加以修复，可能会导致几种生物 影响包括细胞死亡、突变和癌症。人类疾病， 着色性干皮病是DNA修复能力降低的一个例证 导致更高的细胞致死率，更高的突变频率 以及罹患癌症的倾向。紫外线诱导的DNA损伤的修复 由&gt；10种不同基因产物在一种 这一过程称为核苷酸切除修复。有越来越多的证据表明 DNA修复能力，就像任何表型特征一样，是异质性的 分布在人类群体中。因此，某些人 在DNA修复能力低的人群中，可能更容易发生 对环境遗传毒性物质的不良生物效应，如 作为紫外线。本研究的目标是验证并应用于 人群暴露和易感性的几个生物标志物 环境诱变剂、紫外线。为了实现这一目标，我们 将检测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。更具体地说， 患者队列将由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 很多年了。两个主要的年龄无关的亚组将是那些患有 多发性皮肤癌(MSC)，(6岁或以上)和患者的部位 皮肤癌聚集在特定的身体表面。所有的病人都会 与年龄/性别匹配的对照组配对。我们将检验这一假设 DNA修复能力和体内高突变频率将与 使用两种DNA修复分析(SA1和2)增加皮肤癌风险，a 细胞毒性试验(SA3)和体内突变体的测定 体细胞基因(次黄嘌呤磷酸核糖转移酶， HPRT)(SA4)。最后，对分离的突变克隆的修复的体外研究 将定义个体内克隆间的异质性 对紫外线损伤的敏感性(SA6)。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。

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.