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

描述（由申请人提供）：阿司匹林和其他非甾体抗炎药（NSAID）是有效的化学预防剂，可预防结直肠腺瘤（结直肠癌的前体）。NSAID通过抑制环加氧酶（考克斯）1和2（前列腺素合成途径中的关键酶）发挥其化学预防作用。最初的研究表明，前列腺素合成的遗传变异可以影响结直肠癌的发生。考克斯酶的主要下游产物之一是前列腺素E2（PGE 2）。PGE 2是结肠直肠癌中表达上调最多的前列腺素，实验研究直接表明PGE 2与结肠直肠肿瘤的发生有关。最近的研究表明，前列腺素E2信号可以激活表皮生长因子受体（EGFR）信号，第二个途径的关键重要性，在olorectal癌的发生。本研究将评估结直肠腺瘤与前列腺素/EGFR通路中酶、受体和信号分子遗传变异之间的相关性。我们将重点关注以下蛋白质：a）调节PGE 2水平（前列腺素E合成酶（PGES）和15-羟基前列腺素脱氢酶（PGDN）; B）在细胞表面与PGE 2结合（受体EP 1、EP 2和EP 4）;或c）参与PGE 2与EGFR信号传导的交叉作用（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、体力活动和NSAID使用的信息。所有患者在诊断前均接受了完整的结肠镜检查并完成了问卷调查。已经对几个靶基因进行了重新测序，用于多态性发现（PGES、EP 1、2和4、EGFR），其他靶基因（PGDN、Src）的重新测序正在进行中。我们提出了一个研究设计，最大限度地利用现有的信息，前列腺素/EGFR途径的遗传变异性，通过检查常见的单倍型与标签SNP，以及特定的候选多态性。作为次要目的，将研究与NSAID使用的相互作用，以确定遗传学定义的亚组的反应。还将评估基因-基因相互作用，全面分析遗传变异在这一途径中的作用。本研究采用成本效益的方法来解决前列腺素/EGFR途径的遗传变异性和结直肠肿瘤风险的研究问题。它建立在过去成功的合作以及有希望的初步数据的基础上，并为新的研究人员提供培训。前列腺素/EGFR通路的遗传变异研究将为结直肠癌发生的复杂过程提供深入了解，并增加对NSAID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.