Single nucleotide polymorphisms in the IGF-IRS pathway are associated with outcome in mCRC patients enrolled in the FIRE-3 trial.
Single nucleotide polymorphisms in the IGF-IRS pathway are associated with outcome in mCRC patients enrolled in the FIRE-3 trial.
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DOI：
10.1002/ijc.30715
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发表时间：
2017-07-15
影响因子：
6.4
通讯作者：
Lenz HJ
中科院分区：
文献类型：
--
作者：
Schirripa M;Zhang W;Heinemann V;Cao S;Okazaki S;Yang D;Loupakis F;Berger MD;Ning Y;Miyamoto Y;Suenaga M;Gopez RF;West JD;Hanna D;Barzi A;Falcone A;Stintzing S;Lenz HJ
胰岛素样生长因子（IGF）/IGF受体通路及其支架蛋白胰岛素受体底物（IRS）1和IRS 2是转移性结直肠癌（mCRC）代谢和进展的关键调节因子。该研究的目的是在入组FIRE-3试验的mCRC患者中鉴定IRS 1、IRS 2、IGF 1和IGF-1 R SNP之间的预测和预后标志物。在FIRE-3试验中，通过PCR/直接测序分析了IRS的4个SNP（IRS 1 rs 1801278、rs 1801123; IRS 2 rs 1805097、rs 2289046）和IGF 1-IGFR 1的4个SNP（rs6214、rs6220、rs 2946834、rs 2016347）。通过Kaplan-Meier方法和log-rank检验，在总体人群和根据RAS状态和治疗组的亚组中评估SNP与PFS和OS的关系。在总体人群中，IRS 1 rs 1801123 C/-携带者（N= 105）的OS显著低于T/T（N=464）。（HR=1.32 [95%CI 1.03-1.70]，p=0.029）和多变量。在RAS野生型中观察到类似的结果。在单变量（HR=0.77 [95%CI 0.64-0.92]，p=0.004）和多变量中，与C/C（N=257）相比，IGF 1 rs 2946834 T/-变体患者（N= 280）的PFS改善。在RAS野生型亚组中，IGF 1 rs 2946834 T/-携带者显示出比C/C更好的PFS和OS（PFS的单变量HR =0.65 [95%CI 0.51-0.81]，p<0.001; PFS的多变量HR =0.63 [95%CI 0.50-0.81]，p<0.001）。IRS 1 rs 1801123 SNP被确定为mCRC的新预后标志物。IGF 1 rs 2946834在总体人群和RAS野生型患者中被证实为预后因素。我们的研究结果强调了IGF下游信号通路在RAS野生型mCRC患者中的重要性。
The Insulin-like growth factor (IGF)/IGF-receptor pathway with its scaffolding proteins Insulin Receptor Substrate (IRS)1 and IRS2 are crucial regulators of metabolism and progression in metastatic colorectal cancer (mCRC). The goal of the study was the identification of predictive and prognostic markers among IRS1, IRS2, IGF1 and IGF-1R SNPs in mCRC patients enrolled in the FIRE-3 trial. Four SNPs of IRS (IRS1 rs1801278, rs1801123; IRS2 rs1805097, rs2289046) and 4 SNPs of IGF1-IGFR1 (rs6214, rs6220, rs2946834, rs2016347) were analyzed by PCR/direct-sequencing in the FIRE-3 trial. The relation of SNPs with PFS and OS was evaluated through Kaplan-Meier method and log-rank test in the overall population and in subgroup according to RAS status and treatment arm. In the overall population IRS1 rs1801123 C/- carriers (N= 105) achieved significantly worse OS compared to T/T (N=464) in univariate (HR=1.32 [95%CI 1.03–1.70], p=0.029) and in multivariable. Similar results were observed among RAS wild type. Patients with IGF1 rs2946834 T/- variant (N= 280) achieved improved PFS compared to C/C (N=257) in univariate (HR=0.77 [95%CI 0.64–0.92], p=0.004) and in multivariable. In the RAS wild-type subgroup IGF1 rs2946834 T/- carriers showed better PFS and OS compared to C/C (univariate HR for PFS=0.65 [95%CI 0.51–0.81], p<0.001; multivariable HR for PFS=0.63 [95%CI 0.50–0.81], p<0.001). IRS1 rs1801123 SNP was identified as a new prognostic marker for mCRC. IGF1 rs2946834 was confirmed as prognostic factor in the overall population and in RAS wild type patients. Our findings underline the importance of IGF downstream signaling pathway in RAS wild-type mCRC patient.
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影响因子：
3.7
作者：
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Dear PH
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11.2
作者：
Buck, Elizabeth;Eyzaguirre, Alexandra;Ji, Qun-Sheng
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