Wilkening Stefan, Tavelin Björn, Canzian Federico, Enquist Kerstin, Palmqvist Richard, Altieri Andrea, Hallmans Göran, Hemminki Kari, Lenner Per, Försti Asta
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
Carcinogenesis. 2008 Jun;29(6):1202-6. doi: 10.1093/carcin/bgn101. Epub 2008 Apr 30.
There is strong evidence that cancer-associated inflammation promotes tumor growth and progression. This is especially true for colorectal cancer (CRC). Interleukins (ILs) are important modulators for inflammation. We examined whether promoter polymorphisms in key IL genes (IL4, IL4R, IL6, IL8 and IL10) are associated with the risk or clinical outcome of CRC. Five single-nucleotide polymorphisms (SNPs) were analyzed in genomic DNA from a cohort including 308 Swedish incident cases of CRC with data on Dukes' stage and up to 16 years of follow-up and 585 healthy controls. The selected SNPs have previously been shown to be functional and/or associated with cancer. None of the analyzed SNPs associated with the risk of CRC. When stratifying by tumor stage, significantly more patients carrying at least one G allele of IL10-1082 had tumors with Dukes' stages A + B than with stages C + D (P(trend) = 0.035 for genotype distribution). Analyzing associations with overall survival time, we found the rare T allele of IL4-590 to be related to a longer survival [CT versus CC Cox proportional hazard ratio 0.69, 95% confidence intervals 0.46-1.03, TT versus CC 0.32 (0.10-1.03)]. For IL6-174, the CG genotype was associated with a longer survival when compared with the CC genotype [0.64 (0.40-1.01)]. The present study was particularly suitable for survival analysis because all patients were sampled before the diagnosis of CRC. Our results suggest that the SNPs IL4-590 and IL6-174 may be useful markers for CRC prognosis. The predicted biological effect of these SNPs in relation to promotion of cancer progression is consistent with the observed increased survival time.
有强有力的证据表明，癌症相关炎症会促进肿瘤生长和进展。这在结直肠癌（CRC）中尤为如此。白细胞介素（ILs）是炎症的重要调节因子。我们研究了关键IL基因（IL4、IL4R、IL6、IL8和IL10）的启动子多态性是否与CRC的风险或临床结局相关。在一个队列的基因组DNA中分析了五个单核苷酸多态性（SNP），该队列包括308例瑞典初发CRC病例，这些病例有Dukes分期数据且随访长达16年，以及585名健康对照。所选的SNP先前已被证明具有功能性和/或与癌症相关。所分析的SNP均与CRC风险无关。按肿瘤分期分层时，携带IL10 - 1082至少一个G等位基因的患者中，处于Dukes分期A + B期的肿瘤患者明显多于处于C + D期的患者（基因型分布的P（趋势）= 0.035）。在分析与总生存时间的关联时，我们发现IL4 - 590的罕见T等位基因与更长的生存期相关[CT与CC的Cox比例风险比为0.69，95%置信区间为0.46 - 1.03，TT与CC为0.32（0.10 - 1.03）]。对于IL6 - 174，与CC基因型相比，CG基因型与更长的生存期相关[0.64（0.40 - 1.01）]。本研究特别适合进行生存分析，因为所有患者均在CRC诊断之前采样。我们的结果表明，SNP IL4 - 590和IL6 - 174可能是CRC预后的有用标志物。这些SNP在促进癌症进展方面的预测生物学效应与观察到的生存时间延长一致。
