Prostaglandin Synthesis, Genetics and Colorectal Cancer

阿司匹林和其他非甾体类抗炎药（NSAID）似乎是有效的化学预防剂对结直肠癌的发生。公认的NSAID靶点是环氧合酶-1和-2（COX 1和2，或PTGS 1和2），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关联和遗传变异性的酶和受体与合成的arylandins和相关的花生四烯酸代谢产物。我们已经确定了这些途径中关键蛋白的多态性和单倍型。靶蛋白包括PTGS 1和2、血栓素、前列环素、PGD 2和PGE 2脱氢酶、5、12-和15-脂氧合酶（ALOX 5、ALOX 12和ALOX 15）、PGE 2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2004例对照，以及827例直肠癌病例和1031例对照。参与者被招募作为两个多中心，基于人群的病例对照研究的一部分，其中获得了有关健康状况，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NSAID使用的信息。我们建议使用一种研究设计，通过检查测序基因的全基因单倍型（例如，PTGS 1、PTGS 2、ALOX 12、ALOX 15、PGE 2合酶和PGE 2受体），以及具有功能影响支持证据的变体的候选多态性方法。将研究NSAID使用和膳食脂肪酸摄入的相互作用，以确定遗传定义亚组的反应。使用生化分析，我们还将建立在几个关键蛋白质的多态性的酶和药理学的影响。该生化信息将用于告知基因分型结果和统计分析。这项合作研究的结果将为前列腺素或类花生酸合成的遗传变异在结直肠癌发生和化学预防中的作用提供有力的测试。他们还将以最大化利益和最小化毒性的方式推进化学预防的定制。

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.