Genetic Study of Prostaglandin Synthesis/EGFR and Risk of Colorectal Neoplasia

描述(申请人提供)：阿司匹林和其他非类固醇抗炎药(NSAIDs)是有效的结直肠腺瘤的化学预防药物，结直肠癌的前驱。非甾体抗炎药通过抑制前列腺素合成途径中的关键酶环氧合酶(COX)1和2发挥化学预防作用。初步研究表明，前列腺素合成的遗传变异可能会影响结直肠癌的发生。COX酶的主要下游产物之一是前列腺素E2(PGE2)。PGE2是结直肠癌中表达最高的前列腺素，实验研究直接表明PGE2参与了结直肠癌的发生发展。最近的研究表明，PGE2信号可以激活表皮生长因子受体(EGFR)信号，这是在直肠癌发生中起关键作用的第二条途径。本研究将评估结直肠腺瘤与前列腺素/EGFR途径中酶、受体和信号分子的遗传变异性之间的关系。我们将集中于：a)调节PGE2水平的蛋白质(前列腺素E合成酶(PGES)和15-羟基前列腺素脱氢酶(PgDn)；b)与细胞表面的PGE2结合(受体EP1、EP2和EP4)；或c)参与PGE2与EGFR信号的串扰(Src和EGFR)。我们将在现有的病例对照研究中对540例腺瘤病例和640例无息肉对照的个体进行基因分型。参与者是通过明尼苏达州的胃肠病学实践招募的，并获得了有关健康状况、家族史、饮食摄入量、体力活动和非甾体抗炎药使用的信息。所有患者都接受了全面的结肠镜检查，并在诊断前完成了问卷调查。几个靶基因(pGES，EP1，2，和4，EGFR)已经被重新测序，其他靶基因(PgDn，Src)的重新测序正在进行中。我们提出了一项研究设计，通过检查带有标签SNPs的常见单倍型以及特定的候选多态，最大化关于前列腺素/EGFR途径中遗传可变性的可用信息。作为次要目标，将调查与非甾体抗炎药使用的相互作用，以确定基因定义的亚组的反应。还将评估基因与基因的相互作用，全面分析遗传变异在这一途径中的作用。这项研究使用了一种经济有效的方法来解决前列腺素/EGFR途径中的遗传变异性和结直肠肿瘤风险的研究问题。它建立在过去成功合作的基础上，以及有希望的初步数据，并为新的调查人员提供培训。对前列腺素/EGFR途径的遗传变异的研究将有助于深入了解结直肠癌发生的复杂过程，并增加对非甾体抗炎药化学预防的药物遗传学的理解。

DESCRIPTION (provided by applicant): Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are effective chemopreventive agents against colorectal adenomas, precursors of colorectal cancer. NSAIDs exert their chemopreventive effects through the inhibition of the cyclooxygenases (COX)1 and 2, key enzymes in the prostaglandin synthesis pathway. Initial studies suggest that genetic variation in prostaglandin synthesis can affect colorectal carcinogenesis. One of the main downstream products of the COX enzymes is prostaglandin E2 (PGE2). PGE2 is the most upregulated prostaglandin in colorectal cancer, and experimental studies directly implicate PGE2 in the development of colorectal neoplasia. Recent studies have shown that PGE2 signaling can activate epidermal growth factor receptor (EGFR) signaling, a second pathway of key importance in olorectal carcinogenesis. This study will evaluate the association between colorectal adenomas and genetic variability in enzymes, receptors, and signaling molecules in the prostaglandin/EGFR pathways. We will focus on proteins that: a) regulate PGE2 levels (prostaglandin E synthase (PGES) and 15- hydroxyprostaglandin dehydrogenase (PGDN); b) bind to PGE2 at the cell surface (receptors EP1, EP2, and EP4); or c) are involved in PGE2 cross-talk with EGFR signaling (Src and EGFR). We will genotype individuals in an existing case-control study of 540 adenoma cases and 640 polyp-free controls. Participants were recruited through gastroenterology practices in Minnesota and information on health status, family history, dietary intake, physical activity, and NSAID use has been obtained. All patients underwent a full colonoscopy and completed questionnaires prior to diagnosis. Several of the target genes have been resequenced for polymorphism discovery (PGES, EP1, 2, and 4, EGFR) and resequencing of the other target genes (PGDN, Src) is underway. We propose a study design that maximizes available information regarding genetic variability in the prostaglandin/EGFR pathways by examining common haplotypes with tag SNPs, as well as specific candidate polymorphisms. As a secondary aim, interactions with NSAID use will be investigated to determine responses of genetically-defined subgroups. Gene-gene interactions will also be evaluated, providing a comprehensive analysis of the role of genetic variation in this pathway. This study uses a cost-effective approach to address the research question of genetic variability in the prostaglandin/EGFR pathways and risk of colorectal neoplasia. It builds on past successful collaborations, as well as promising preliminary data, and provides training for a new investigator. This study of genetic variation in the prostaglandin/EGFR pathway will provide insights into the complex process of colorectal carcinogenesis, and increase understanding of the pharmacogenetics of NSAID chemoprevention.