Prostaglandin Synthesis, Genetics and Colorectal Cancer

阿司匹林和其他非甾体抗炎药（NSAIDs）似乎是有效的化学预防剂对结直肠癌的发生。公认的非甾体抗炎药靶点是环氧化酶-1和-2 (COX1和2，或PTGS1和2)，它们是花生四烯酸酯转化为前列腺素（PG）信号分子的关键酶。这项跨学科研究将评估结肠癌和直肠癌与前列腺素和相关花生四烯酸代谢物合成相关的酶和受体的遗传变异之间的关系。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PTGS1和2、血栓素、前列腺素、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。我们将对两个现有病例对照研究人群进行基因分型，其中包括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。参与者被招募为两项多中心、基于人群的病例对照研究的一部分，其中获得了健康状况、家族史、饮食因素（包括n-6和n-3脂肪酸的摄入量）、身体活动和非甾体抗炎药使用的信息。我们建议采用一种研究设计，通过检测已测序基因的全基因单倍型（如PTGS1、PTGS2、ALOX12、ALOX15、PGE2合成酶和PGE2受体），最大限度地利用这些关键途径的遗传变异性信息，并采用候选多态性方法研究具有功能影响证据的变异。将研究非甾体抗炎药使用和膳食脂肪酸摄入量之间的相互作用，以确定基因定义亚群的反应。利用生化分析，我们还将建立几个关键蛋白质多态性的酶和药理学影响。这些生化信息将用于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二十烷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。它们还将以一种使效益最大化和毒性最小化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.