Küry Sébastien, Buecher Bruno, Robiou-du-Pont Sébastien, Scoul Catherine, Colman Hélène, Le Neel Tanguy, Le Houérou Claire, Faroux Roger, Ollivry Jean, Lafraise Bernard, Chupin Louis-Dominique, Sébille Véronique, Bézieau Stéphane
Service de Génétique Médicale, Pôle de Biologie, CHU de Nantes, 9 quai Moncousu, Nantes, 44093 cedex 1, France.
BMC Cancer. 2008 Nov 7;8:326. doi: 10.1186/1471-2407-8-326.
Sporadic colorectal cancers (CRC) are multifactorial diseases resulting from the combined effects of numerous genetic, environmental and behavioral risk factors. Genetic association studies have suggested low-penetrance alleles of extremely varied genes to be involved in susceptibility to CRC in Caucasian populations.
Through a large genetic association study based on 1023 patients with sporadic CRC and 1121 controls, we tested a panel of these low-penetrance alleles to find out whether they could determine "genotypic profiles" at risk for CRC among individuals of the French population. We examined 52 polymorphisms of 35 genes - drawn from inflammation, xenobiotic detoxification, one-carbon, insulin signaling, and DNA repair pathways - for their possible contribution to colorectal carcinogenesis. The risk of cancer associated with these polymorphisms was assessed by calculation of odds ratios (OR) using multivariate analyses and logistic regression.
Whereas all these polymorphisms had previously been found to be associated with CRC risk, especially in Caucasian populations, we were able to replicate the association for only five of them. Three SNPs were shown to increase CRC risk: PTGS1 c.639C>A (p.Gly213Gly), IL8 c.-352T>A, and MTHFR c.1286A>C (p.Ala429Glu). On the contrary, two other SNPs, PLA2G2A c.435+230C>T and PPARG c.1431C>T (p.His477His), were associated with a decrease in CRC risk. Further analyses highlighted genotypic combinations having a greater predisposing effect on CRC (OR 1.97, 95%CI 1.31-2.97, p = 0.0009) than the allelic variants that were examined separately.
The identification of CRC-predisposing combinations, composed of alleles PTGS1 c.639A, PLA2G2A c.435+230C, PPARG c.1431C, IL8 c.-352A, and MTHFR c.1286C, highlights the importance of inflammatory processes in susceptibility to sporadic CRC, as well as a possible crosstalk between inflammation and one-carbon pathways.
散发性结直肠癌（CRC）是由众多遗传、环境和行为风险因素共同作用导致的多因素疾病。基因关联研究表明，在白种人群中，多种基因的低 penetrance 等位基因与 CRC 易感性有关。
通过一项基于 1023 例散发性 CRC 患者和 1121 例对照的大型基因关联研究，我们检测了一组这些低 penetrance 等位基因，以确定它们是否能在法国人群个体中确定 CRC 风险的“基因型谱”。我们检查了来自炎症、外源性解毒、一碳、胰岛素信号和 DNA 修复途径的 35 个基因的 52 个多态性，以评估它们对结直肠癌发生的可能贡献。使用多变量分析和逻辑回归计算比值比（OR）来评估与这些多态性相关的癌症风险。
尽管之前发现所有这些多态性都与 CRC 风险相关，尤其是在白种人群中，但我们仅能重复其中五个的关联。三个单核苷酸多态性（SNP）显示会增加 CRC 风险：PTGS1 c.639C>A（p.Gly213Gly）、IL8 c.-352T>A 和 MTHFR c.1286A>C（p.Ala429Glu）。相反，另外两个 SNP，PLA2G2A c.435+230C>T 和 PPARG c.1431C>T（p.His477His）与 CRC 风险降低相关。进一步分析强调，与单独检查的等位基因变体相比，某些基因型组合对 CRC 具有更大的易感性影响（OR 1.97，95%CI 1.31 - 2.97，p = 0.0009）。
由等位基因 PTGS1 c.639A、PLA2G2A c.435+230C、PPARG c.1431C、IL8 c.-352A 和 MTHFR c.1286C 组成的 CRC 易感组合的鉴定，突出了炎症过程在散发性 CRC 易感性中的重要性，以及炎症与一碳途径之间可能存在的相互作用。
