Prostaglandin Synthesis, Genetics and Colorectal Cancer

描述(申请人提供)：阿司匹林和其他非类固醇炎症药物(NSAIDs)似乎是预防结直肠癌发生的有效化学预防药物。公认的NSAID靶点是环氧合酶-1和-2(COX1和2，或PTGS1和2)，这是花生四烯酸转化为前列腺素(PG)信号分子的关键酶。这项跨学科的研究将评估结肠癌和直肠癌之间的联系，以及与前列腺素和相关的花生四烯酸代谢产物合成有关的酶和受体的遗传变异性。我们已经确定了这些途径中关键蛋白的多态和单倍型。靶蛋白包括PTGS1和2、血栓烷、前列环素、PGD2和PGE2合成酶、5、12和15-脂氧合酶(ALOX5、ALOX12和ALOX15)、PGE2受体和谷胱甘肽过氧化物酶。我们将对两个现有的病例对照研究人群进行基因分型，包括1676例结肠癌病例和827例直肠癌病例，其中结肠癌病例为2004年对照，直肠癌病例为1031对照。参与者被招募为两项多中心、基于人群的病例对照研究的一部分，在这两项研究中，获得了关于健康状况、家族史、饮食因素(包括n-6和n-3脂肪酸的摄入量)、体力活动和非甾体抗炎药使用的信息。我们建议使用一种研究设计，通过检查测序基因(例如，PTGS1、Ptgs2、ALOX12、ALOX15、PGE2合成酶和PGE2受体)的全基因单倍型来最大化关于这些关键途径中的遗传变异性的可用信息，并对具有支持功能影响的证据的变异采用候选多态方法。将调查与非甾体抗炎药使用和膳食脂肪酸摄入量的相互作用，以确定基因定义的亚组的反应。利用生化分析，我们还将确定几个关键蛋白质的多态对酶和药理学的影响。这些生化信息将被用来通知基因分型结果和统计分析。这项合作研究的结果将对前列腺素或二十烷类化合物合成中的遗传变异性在结直肠癌发生和化学预防中的作用提供强有力的测试。他们还将以最大化效益和最小化毒性的方式推进化学预防的定制。

DESCRIPTION (provided by applicant): Aspirin and other non-steroidal inflammatory drugs (NSAIDs) appear to be effective chemopreventive agents against colorectal carcinogenesis. The recognized NSAID targets are cyclooxygenase-1 and -2 (COX1 and 2, or PTGS1 and 2), key enzymes in conversion of arachidonate to prostaglandin (PG) signaling molecules. This interdisciplinary study will evaluate the association between colon and rectal cancer and genetic variability in enzymes and receptors linked to the synthesis of prostaglandins and related arachidonate metabolites. We have identified polymorphisms and haplotypes in key proteins in these pathways. Target proteins include PTGS1 and 2, the thromboxane, prostacyclin, PGD2 and PGE2 synthases, the 5, 12- and 15- lipoxygenases (ALOX5, ALOX12 and ALOX15), PGE2 receptors, and glutathione peroxidases. We will genotype two existing case-control study populations comprising 1676 colon cancer cases with 2004 controls and 827 rectal cancer cases with 1031 controls. Participants were recruited as part of two multi-center, population-based case-control studies in which information on health status, family history, dietary factors (including intakes of n-6 and n-3 fatty acids), physical activity, and NSAID use has been obtained. We propose to use a study design that maximizes available information regarding genetic variability in these key pathways by examining gene-wide haplotypes for sequenced genes (e.g., PTGS1, PTGS2, ALOX12, ALOX15, PGE2 synthase and PGE2 receptors), and a candidate-polymorphism approach for variants with supporting evidence for functional impact. Interactions with NSAID use and dietary fatty acid intakes will be investigated to determine responses of genetically defined subgroups. Using biochemical assays, we will also establish the enzymatic and pharmacological impact of polymorphisms in several key proteins. This biochemical information will be used to inform the genotyping results and the statistical analysis. Results from this collaborative study will provide a powerful test of the role of genetic variability in prostaglandin or eicosanoid synthesis in colorectal carcinogenesis and chemoprevention. They will also advance tailoring of chemoprevention in a way that maximizes benefit and minimizes toxicity.