UDP-GLUCURONOSYLTRANSFERASE GENOTYPE AND CANCER RISK

UDP-葡萄糖醛酸基转移酶基因型和癌症风险

基本信息

批准号：
8064730
负责人：
Philip Lazarus
金额：
$ 50.27万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8064730
关键词：
17p African American Alleles Androstanes Androsterone Arkansas Award Benzo(a)pyrene Biological Assay Butanones C19 steroid Carcinogens Case-Control Studies Caucasians Caucasoid Race Cell Line Chloramphenicol O-Acetyltransferase Code DNA Drug Metabolic Detoxication Eating Endogenous Factors Endometrial Carcinoma Enzymes Estradiol Funding Gene Deletion Gene Expression Genes Genetic Polymorphism Genetic Variation Genomics Genotype Glucuronosyltransferase Glycols Goals Hormones Hospitals Human In Vitro Individual Isoenzymes Kinetics Liver Liver Microsomes Luciferases Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Memorial Sloan-Kettering Cancer Center Metabolism Microsomes Mining New Jersey Oral Oral mucous membrane structure Organ Pathway interactions Phenotype Play Predisposition Prevalence Promoter Regions Prostate Proteins RNA Recruitment Activity Relative (related person)Reporter Genes Research Personnel Reverse Transcriptase Polymerase Chain Reaction Risk Role Sampling Series Site Smoke Smoker Specimen Stanolone Steroids Structure of parenchyma of lung System Testosterone Time Tissues Tobacco Tobacco smoke Tobacco-Associated Carcinogen Universities Urine Variant Xenobiotics base bilirubin uridine-diphosphoglucuronosyl transferase 1A10 cancer epidemiology cancer genetics cancer risk carcinogenesis inhibitor/antagonist man population based programs promoter

项目摘要

DESCRIPTION (provided by applicant): Glucuronidation plays an extremely important role in the metabolism and elimination of a variety of carcinogens and endogenous factors associated with increased risk for cancer. Our studies over the first five years of this award strongly suggest that two UGTs - UGT1A10 and UGT2B17 - play key roles in cancer susceptibility. We have identified prevalent deletion polymorphisms for both UGT1A10 and UGT2B17 that include either part of the proximal promoter region or a large part of the coding sequence, and that the whole-gene UGT2B17*2 deletion allele is associated with significant decreases in liver microsome glucuronidating activities and increased risk for lung adenocarcinoma. Both enzymes are, (1) present in target sites for tobacco-related cancers including the aerodigestive tract and lung and are active against many important metabolites of tobacco smoke carcinogens including BaP and NNK, (2) UGT1A10 is highly active against relevant C18 steroids like estradiol and is widely-expressed in hormone-related tissues, and (3) UGT2B17 is present in prostate and is highly active against relevant C19 steroids including testosterone and dihydrotestosterone. Therefore, both enzymes could potentially play a significant role in the detoxification of relevant substrates in all of these aforementioned sites, and UGT genetic variations like gene deletions could have a significant impact on cancer risk. We hypothesize that UGT1A10 and UGT2B17 polymorphisms that significantly alter activities against exogenous xenobiotics like tobacco carcinogens or endogenous compounds like C18 or C19 steroids are correlated with altered glucuronidation phenotypes, and that they play an important role in cancer risk. It is the goal of this proposal to, (1) characterize these and other potential polymorphisms in the two genes, (2) assess their effect on enzyme function or expression both in vitro and in genotype:phenotype assays, and (3) perform preliminary studies examining their role in cancer risk. These studies will be combined with a careful assessment of the overall importance of UGT1A10- and UGT2B17-glucuronidating activities against a variety of tobacco smoke carcinogens or their metabolites. These studies should significantly impact on the field of cancer genetics and epidemiology as they will enable us to better assess the role of variation in glucuronidation pathways and cancer induction.

描述（由申请人提供）：葡萄糖醛酸化在多种致癌物和与癌症风险增加相关的内源性因素的代谢和消除中起着极其重要的作用。我们在该奖项前五年的研究强烈表明，两种 UGT - UGT1A10 和 UGT2B17 - 在癌症易感性中发挥着关键作用。我们已经确定了 UGT1A10 和 UGT2B17 的普遍删除多态性，包括部分近端启动子区域或大部分编码序列，并且全基因 UGT2B17*2 删除等位基因与肝微粒体葡萄糖醛酸化活性的显着降低相关并增加患肺腺癌的风险。这两种酶：(1) 存在于烟草相关癌症的靶位点，包括呼吸消化道和肺部，并且对烟草烟雾致癌物的许多重要代谢物（包括 BaP 和 NNK）具有活性，(2) UGT1A10 对相关的 C18 类固醇具有高度活性，例如(3) UGT2B17 存在于前列腺中，并且对相关 C19 类固醇具有高度活性，包括睾酮和二氢睾酮。因此，这两种酶可能在上述所有位点的相关底物解毒中发挥重要作用，并且 UGT 遗传变异（例如基因缺失）可能对癌症风险产生重大影响。我们假设 UGT1A10 和 UGT2B17 多态性显着改变针对外源性异生物质（如烟草致癌物）或内源性化合物（如 C18 或 C19 类固醇）的活性，与改变的葡萄糖醛酸化表型相关，并且它们在癌症风险中发挥重要作用。本提案的目标是，(1) 表征这两个基因中的这些和其他潜在多态性，(2) 评估它们对体外和基因型：表型测定中酶功能或表达的影响，以及 (3) 进行初步分析研究检查它们在癌症风险中的作用。这些研究将与对 UGT1A10 和 UGT2B17 葡萄糖醛酸化活性对多种烟草烟雾致癌物或其代谢物的总体重要性的仔细评估相结合。这些研究将对癌症遗传学和流行病学领域产生重大影响，因为它们将使我们能够更好地评估变异在葡萄糖醛酸化途径和癌症诱导中的作用。