UDP-glucuronosyltransferase genes and gender-differences in lung cancer risk

描述(申请人提供)：虽然吸烟是导致绝大多数肺癌的原因，但大多数终生吸烟者不会患上这种疾病。许多研究表明，女性比男性更容易患肺癌，烟草致癌物代谢酶的基因变异可以解释为什么只有一些吸烟者患肺癌，以及为什么女性可能比男性面临更大的风险。来自我们实验室的最新数据表明，UDP-葡萄糖醛酸基转移酶UGT2B17的多态缺失只会增加女性患肺癌的风险(Gallagher ef a/.，2007)。这与UGT2B17是有效烟草致癌物的主要解毒剂这一事实以及包括UGT2B17在内的几种UGT酶的表达受激素调节的事实是一致的。这项应用的总体假设是，UGT1A基因的变异会增加患肺癌的风险，通过使用单倍型方法来综合测试所有UGT1A变异与肺癌的遗传关联，将识别危险等位基因。此外，激素依赖的UGT调节可能是导致不同性别肺癌风险差异的一个重要变量。该项目将使用单倍型来有效和全面地评估UGT1A基因簇中的变异与肺癌风险的关系以及与这种疾病的性别特异性关联。在这些独立研究之前，候选人Carla Gallagher博士和她的主要导师、UGT药物遗传学专家Philip Lazarus博士将通过评估UGT1A5来完成LJGT1A基因参与致癌物质代谢的图景，UGT1A5是唯一尚未进行这一活性测试的UGT1A基因。在特定目标1中，将确定UGT1A5的表达、对烟草致癌物的活性以及编码多态的功能能力。在指导阶段结束后，加拉格尔博士将与她的共同导师M·丹尼尔·法林博士一起接受单倍型遗传学培训，为独立阶段做准备。在具体目标2中，将进行LJGT1A基因与肺癌风险的单倍型关联研究，并将测试特定性别的关联。在具体目标3中，将研究性别对UGT1A酶表达和活性的影响。这项研究将能够识别针对肺癌的筛查、干预和预防的高危个体，并可能澄清肺癌风险的性别差异，以便设计针对性别的干预措施。

DESCRIPTION (provided by applicant): Although cigarette smoking causes the vast majority of lung cancers, most lifetime smokers do not develop this disease. Many studies suggest that women have greater susceptibility than men for lung cancer, and genetic variation in tobacco carcinogen-metabolizing enzymes could explain why only some smokers develop lung cancer and why women may be at a greater risk than men. Recent data from our lab has demonstrated that a polymorphic deletion of a UDP-glucuronosyltransferase, UGT2B17, increases risk for lung cancer exclusively in women (Gallagher ef a/., 2007). This is consistent with the fact that UGT2B17 is a major detoxifier of potent tobacco carcinogens and with the fact that expression of several UGT enzymes, including UGT2B17, are regulated by hormones. The overall hypothesis of this application is that variants in UGT1A genes increase risk for lung cancer and that by using a haplotype approach to comprehensively test all UGT1A variation for genetic association with lung cancer, the risk alleles will be identified. Additionally, hormone-dependent regulation of UGTs may be an important variable resulting in differential risk for lung cancer between sexes. This project will use haplotypes to efficiently and comprehensively evaluate variants in the UGT1A gene cluster for involvement in lung cancer risk and for gender-specific associations with this disease. Prior to these independent studies, the candidate, Dr. Carla Gallagher, together with her primary mentor, Dr. Philip Lazarus, an expert in UGT pharmacogenetics, will complete the picture of the involvement of LJGT1A genes in carcinogen metabolism by evaluating UGT1A5, the only UGT1A gene that has yet to be tested for this activity. In Specific Aim 1, expression, activity against tobacco carcinogens, and functional capacity of coding polymorphisms will be determined for UGT1A5. At the completion of the mentored phase, Dr. Gallagher will train with her co-mentor, Dr. M. Daniele Fallin, in haplotype genetics in preparation for the independent phase. In Specific Aim 2, haplotype association studies of LJGT1A genes and lung cancer risk will be performed, and gender-specific associations will be tested. In Specific Aim 3, the effects of gender on expression and activity of UGT1A enzymes will be examined. This study will enable identification of high-risk individuals for targeted lung cancer screening, intervention, and prevention, and may clarify the gender differences in lung cancer risk for design of gender-specific interventions.