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Single nucleotide polymorphisms in the IGF-IRS pathway are associated with outcome in mCRC patients enrolled in the
Marta Schirripa1, Wu Zhang1, Volker Heinemann2
1Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033.
Abstract:
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 four 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.
Insights
Specific gene variants in the Insulin-like growth factor (IGF) pathway, including IRS1 rs1801123 and IGF1 rs2946834, show prognostic significance in metastatic colorectal cancer (mCRC). These findings highlight the role of IGF signaling in mCRC patient outcomes.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- The Insulin-like growth factor (IGF)/IGF-receptor pathway and its scaffolding proteins, Insulin Receptor Substrate (IRS)1 and IRS2, are critical in regulating metabolism and the progression of metastatic colorectal cancer (mCRC).
- Identifying genetic variations within this pathway may offer insights into predicting patient outcomes.
Purpose of the Study:
- To identify single nucleotide polymorphisms (SNPs) in IRS1, IRS2, IGF1, and IGF-1R that serve as predictive or prognostic markers in mCRC patients.
- To evaluate the association of these SNPs with progression-free survival (PFS) and overall survival (OS) in the FIRE-3 clinical trial cohort.
Main Methods:
- Genotyping of eight SNPs (four in IRS genes and four in IGF1-IGFR1 genes) using PCR and direct sequencing in mCRC patients from the FIRE-3 trial.
- Statistical analysis, including Kaplan-Meier method and log-rank tests, to assess the relationship between SNPs and survival outcomes (PFS and OS).
- Analysis was performed on the overall population and stratified by RAS mutation status and treatment arm.
Main Results:
- The IRS1 rs1801123 SNP (C/- carriers) was associated with significantly worse OS compared to T/T genotype in the overall population and in RAS wild-type patients.
- The IGF1 rs2946834 SNP (T/- variant) was linked to improved PFS and OS compared to the C/C genotype, particularly in the overall population and RAS wild-type subgroup.
- These associations remained significant in both univariate and multivariable analyses.
Conclusions:
- The IRS1 rs1801123 SNP is identified as a novel prognostic marker for mCRC.
- The IGF1 rs2946834 SNP is confirmed as a prognostic factor in mCRC, especially in RAS wild-type patients.
- The study underscores the importance of the IGF downstream signaling pathway in the prognosis of RAS wild-type mCRC.