UDP-GLUCURONOSYLTRANSFERASE GENOTYPE AND CANCER RISK

描述(由申请人提供)：葡萄糖醛酸化在新陈代谢和消除与癌症风险增加相关的各种致癌物质和内源性因素方面发挥着极其重要的作用。我们在该奖项前五年的研究有力地表明，两种UGT-UGT1A10和UGT2B17-在癌症易感性中发挥关键作用。我们发现UGT1A10和UGT2B17存在普遍的缺失多态，包括近端启动子区域的一部分或编码序列的大部分，并且UGT2B17*2全基因缺失等位基因与肝微粒体葡萄糖醛酸化活性显著降低和肺腺癌风险增加有关。这两种酶是：(1)存在于烟草相关癌症的靶点，包括呼吸消化道和肺，对烟草烟雾致癌物质的许多重要代谢物，包括BaP和NNK具有活性；(2)UGT1A10对相关的C18类固醇如雌二醇具有高度活性，并在激素相关组织中广泛表达；以及(3)UGT2B17存在于前列腺，对相关的C19类固醇，包括睾酮和双氢睾酮具有高度的活性。因此，这两种酶都可能在上述所有位点的相关底物的解毒过程中发挥重要作用，而UGT基因变异(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基因的多态显著改变了对烟草致癌物等外源性外源物质或C18或C19类固醇等内源性化合物的活性，这些多态与葡萄糖醛酸化表型的改变相关，并且它们在癌症风险中发挥重要作用。这项建议的目标是：(1)表征这两个基因中的这些和其他潜在的多态；(2)评估它们对酶功能或表达的影响，在体外和在基因中：表型分析；以及(3)进行初步研究，探讨它们在癌症风险中的作用。这些研究将结合对UGT1A10和UGT2B17-葡萄糖醛酸化活动对各种烟草烟雾致癌物质或其代谢物的总体重要性的仔细评估。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。

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.