Division of Epidemiology, Department of Medicine, Vanderbilt University, Nashville, TN, USA.
Cancer Prev Res (Phila). 2012 Jun;5(6):855-63. doi: 10.1158/1940-6207.CAPR-11-0459. Epub 2012 May 2.
Colorectal cancer (CRC) is the second leading cause of cancer-related death and usually arises from colorectal polyps. Screening and removal of polyps reduce mortality from CRC. Colorectal polyps are known to aggregate in families; however the genetic determinants for risk of polyps are unknown. In addition, it has been shown that nonsteroidal anti-inflammatory drug (NSAID) use decreases the risk of CRC and the incidence and size of polyps. In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to evaluate selected genes from the prostaglandin (PG) metabolism and signaling pathways for association with risk of polyps and for interactions with NSAIDs. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian polyp cases and 3,285 Caucasian controls. We carried out multivariable logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis. We detected association signals in the genes PGE receptor 3 (PTGER3) and 15-hydroxyprostaglandin dehydrogenase (HPGD), both strong biologic candidates for influence on polyp risk. We did not observe the previously reported effects and effect modification in PG-endoperoxide synthase 2 (PTGS2), PGE receptor 2 (PTGER2), or PGE receptor 4 (PTGER4), although we did observe a single nucleotide polymorphism in PTGER2 associated with risk of multiple adenomas. We also observed effect modification of the HPGD signal by NSAID exposure.
结直肠癌（CRC）是癌症相关死亡的第二大主要原因，通常源于结直肠息肉。筛查和切除息肉可降低 CRC 的死亡率。已知结直肠息肉在家族中聚集；然而，息肉风险的遗传决定因素尚不清楚。此外，已经表明非甾体抗炎药（NSAID）的使用降低了 CRC 的风险以及息肉的发生率和大小。在这项研究中，我们使用了田纳西州结肠息肉研究和田纳西州-印第安纳州腺瘤复发研究的数据，来评估前列腺素（PG）代谢和信号通路中的选定基因与息肉风险的关联，并评估其与 NSAID 的相互作用。我们的设计包括发现和复制阶段，共有 2551 例白种人息肉病例和 3285 例白种人对照。我们进行了多变量逻辑回归分析，以检验发现和复制阶段的关联，并进一步通过荟萃分析检查结果。我们在前列腺素 E 受体 3（PTGER3）和 15-羟基前列腺素脱氢酶（HPGD）基因中检测到关联信号，这两个基因都是对息肉风险有重要影响的生物学候选基因。我们没有观察到以前报道的 PG-内过氧化物合酶 2（PTGS2）、前列腺素 E 受体 2（PTGER2）或前列腺素 E 受体 4（PTGER4）中的效应和效应修饰，尽管我们确实观察到了 PTGER2 中的一个单核苷酸多态性与多发性腺瘤的风险相关。我们还观察到 NSAID 暴露对 HPGD 信号的效应修饰。
