GENETIC SUSCEPTIBILITY TO TOBACCO RELATED CARCINOGENESIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。有充分的证据表明，遗传性状在个体对烟草相关癌症的易感性中起着关键作用。最近，在DNA修复基因中发现了一些编码氨基酸变化的序列变异（多态性）；然而，人们对它们对暴露于烟草烟雾引起的基因损伤的细胞反应的影响知之甚少。我们将研究几种DNA修复基因（如XRCC1、XRCC3和XPD）的多态性在三种主要DNA修复途径中的作用，同时考虑生物转化酶基因中有影响的多态性的作用。我们假设DNA修复基因中编码氨基酸变化的遗传多态性会影响DNA修复的效率，从而导致吸烟在染色体和基因水平上增加遗传损伤的积累。我们将在400名无症状吸烟者和400名健康非吸烟者中测试我们的假设。我们将使用暴露（血浆中可替宁水平）和生物效应（细胞遗传终点和体细胞基因突变）的生物标志物来研究DNA修复多态性对诱导遗传损伤的影响。此外，在受控的体外实验中，我们将确定这些多态性在暴露于模型烟草致癌物的培养细胞中诱导遗传损伤的作用。这项研究也将对理解这些多态性在吸烟相关癌症风险中的作用具有重要意义。从这项研究中获得的知识对于为不同的吸烟易感性提供新的机制解释至关重要。

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. It is well documented that inherited genetic traits play a critical role in individual susceptibility to tobacco-related cancers. Recently, several sequence variations (polymorphisms) coding for amino acid changes in DNA repair genes have been identified; however, little is known about their effects on cellular responses to genetic damage induced by exposure to tobacco smoke. We will investigate the roles of polymorphisms in several DNA repair genes (e.g. XRCC1, XRCC3, and XPD) involved in three major DNA repair pathways), while taking into consideration the role of influential polymorphisms in genes for biotransformation enzymes. We hypothesize that inherited polymorphisms coding for amino acid changes in DNA repair genes affect the efficiency of DNA repair, thus leading to increased accumulation of genetic damage in response to smoking at both the chromosomal and gene levels. We will test our hypothesis in a population of 400 non-symptomatic smokers and 400 healthy non-smokers. We will use biomarkers of exposure (cotinine levels in plasma) and of biological effects (cytogenetic end points and somatic cell gene mutations) to investigate the influence of DNA repair polymorphisms on the induction of genetic damage. In addition, in controlled in vitro experiments, we will determine the roles of these polymorphisms in the induction of genetic damage in cultured cells exposed to model tobacco carcinogens. The study will also have significant implications for understanding the role of these polymorphisms in smoking-associated cancer risk. Knowledge gained from the study is critical for providing new mechanistic explanations for differential susceptibility to tobacco smoking.