Slattery Martha L, Wolff Roger K, Curtin Karen, Fitzpatrick Frank, Herrick Jennifer, Potter John D, Caan Bette J, Samowitz Wade S
Department of Medicine, University of Utah, Salt Lake City, UT 84108, USA.
Mutat Res. 2009 Jan 15;660(1-2):12-21. doi: 10.1016/j.mrfmmm.2008.10.001. Epub 2008 Oct 15.
Variation in genes associated with serum levels of proteins may be useful for examining specific disease pathways. Using data from a large study of colon cancer, we examine genetic variants in insulin, inflammation, estrogen, metabolizing enzymes, and energy homeostasis genes to explore associations with microsatellite instability (MSI), CpG Island methylator phenotype (CIMP), mutations of p53 in exons 5 through 8, and mutations in codons 12 and 13 of Ki-ras. Insulin-related genes were associated with CIMP-positive and MSI tumors, with the strongest associations among aspirin users. The Fok1 vitamin D receptor (VDR) polymorphism was associated with CIMP-positive/Ki-ras-mutated tumors; the Poly A and CDX2 VDR polymorphisms were associated only with Ki-ras-mutated tumors. NAT2 was associated with CIMP-positive/Ki-ras-mutated tumors but not with MSI tumors. The TCF7L2 rs7903146 polymorphism was associated with p53 mutated tumors. Most associations varied by recent aspirin/NSAID use: IL6 rs1800796 and rs1800795 polymorphisms were associated inversely with tumor mutations in the presence of aspirin/NSAIDs; POMC significantly reduced risk of Ki-ras-mutated tumors when aspirin/NSAIDs were not used; the TCF7L2 rs7903146 was associated with reduced risk of Ki-ras-mutated tumors in the presence of aspirin and increased risk in the absence of aspirin. These data, although exploratory, identify specific tumor subsets that may be associated with specific exposures/polymorphism combinations. The important modifying effects of aspirin/NSAIDs on associations with genetic polymorphisms reinforce the underlying role of inflammation in the etiology of colon cancer.
与血清蛋白水平相关的基因变异可能有助于研究特定疾病途径。利用一项大型结肠癌研究的数据，我们检测了胰岛素、炎症、雌激素、代谢酶和能量稳态基因中的遗传变异，以探索其与微卫星不稳定性（MSI）、CpG岛甲基化表型（CIMP）、p53基因外显子5至8的突变以及Ki-ras密码子12和13的突变之间的关联。胰岛素相关基因与CIMP阳性和MSI肿瘤相关，在阿司匹林使用者中关联最强。Fok1维生素D受体（VDR）多态性与CIMP阳性/Ki-ras突变肿瘤相关；Poly A和CDX2 VDR多态性仅与Ki-ras突变肿瘤相关。NAT2与CIMP阳性/Ki-ras突变肿瘤相关，但与MSI肿瘤无关。TCF7L2 rs7903146多态性与p53突变肿瘤相关。大多数关联因近期使用阿司匹林/非甾体抗炎药而有所不同：在使用阿司匹林/非甾体抗炎药的情况下，IL6 rs1800796和rs1800795多态性与肿瘤突变呈负相关；在未使用阿司匹林/非甾体抗炎药时，POMC可显著降低Ki-ras突变肿瘤的风险；在使用阿司匹林的情况下，TCF7L2 rs7903146与降低Ki-ras突变肿瘤的风险相关，而在未使用阿司匹林时则与风险增加相关。这些数据虽然具有探索性，但确定了可能与特定暴露/多态性组合相关的特定肿瘤亚组。阿司匹林/非甾体抗炎药对与基因多态性关联的重要修饰作用强化了炎症在结肠癌病因学中的潜在作用。
