Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States.
Cancer Epidemiol. 2012 Apr;36(2):206-11. doi: 10.1016/j.canep.2011.05.013. Epub 2011 Aug 17.
Insulin-like growth factor (IGF)-axis genes plays a critical role in cancer development and progression via their impact on the RAS/MAPK/ERK and PI3K/AKT/mTOR signaling pathways. We hypothesized that IGF-axis genetic variants modify individual susceptibility to pancreatic cancer.
We retrospectively genotyped 41 single-nucleotide polymorphisms of 10 IGF-axis genes (IGF1, IGF2, IGF1R, IGF2R, IGFBP1, IGFBP3, IGFBP5, IRS1, IRS2, and IRS4) in 706 pancreatic cancer patients and 706 cancer-free controls using Sequenom and TaqMan technology. The association between genotype and pancreatic cancer risk was evaluated using multivariate logistic regression. A P value ≤.007 at a false discovery rate of 10% was set as the significance level.
We observed that the IGF1 *10212C>A and Ex4+2776G>A and IGF1R IVS2-70184A>G and IVS2+46329T>C variant genotypes were significantly associated with decreased pancreatic cancer risk (odds ratio [OR] range, 0.60-0.75) and that IGFBP1 Ex4+111A>G (I253M) was significantly associated with increased pancreatic cancer risk (OR=1.46) after adjusted for other risk factors and multiple comparisons (P≤.007). IGF2R and IGFBP3 variant haplotypes were associated with increased and decreased pancreatic cancer risk, respectively (P<.001). We also observed a weak interaction of the IGF1R IVS2+46329T>C and IGF2R Ex45+11C>T (L2222L) genotypes with diabetes (P(interaction)=.05) and interaction of IGF2R and IRS1 genotypes with alcohol consumption (P(interaction)=.03 and .019, respectively) on increased pancreatic cancer risk.
These findings support our hypothesis that polymorphic variants of IGF-axis genes act alone or jointly with other risk factors to affect susceptibility to pancreatic cancer.
胰岛素样生长因子（IGF）-轴基因通过其对 RAS/MAPK/ERK 和 PI3K/AKT/mTOR 信号通路的影响，在癌症的发生和发展中起着关键作用。我们假设 IGF 轴遗传变异会改变个体对胰腺癌的易感性。
我们使用 Sequenom 和 TaqMan 技术，对 706 例胰腺癌患者和 706 例无癌症对照者的 10 个 IGF 轴基因（IGF1、IGF2、IGF1R、IGF2R、IGFBP1、IGFBP3、IGFBP5、IRS1、IRS2 和 IRS4）的 41 个单核苷酸多态性进行了回顾性基因分型。使用多变量逻辑回归评估基因型与胰腺癌风险之间的关联。在假发现率为 10%的情况下，将 P 值≤.007 设定为显著性水平。
我们发现 IGF1*10212C>A 和 Ex4+2776G>A 以及 IGF1R IVS2-70184A>G 和 IVS2+46329T>C 变异基因型与胰腺癌风险降低显著相关（比值比范围为 0.60-0.75），IGFBP1 Ex4+111A>G（I253M）与胰腺癌风险增加显著相关（OR=1.46），校正其他危险因素和多次比较后（P≤.007）。IGF2R 和 IGFBP3 变异单倍型分别与胰腺癌风险的增加和降低相关（P<.001）。我们还观察到 IGF1R IVS2+46329T>C 和 IGF2R Ex45+11C>T（L2222L）基因型与糖尿病之间存在较弱的交互作用（P（交互）=0.05），IGF2R 和 IRS1 基因型与饮酒之间存在交互作用（P（交互）=0.03 和 0.019），这会增加患胰腺癌的风险。
这些发现支持我们的假设，即 IGF 轴基因的多态性变异单独或与其他危险因素共同作用，影响对胰腺癌的易感性。
