Single nucleotide polymorphisms in the IGF‐IRS pathway are associated with outcome in mCRC patients enrolled in the FIRE‐3 trial
Open accessAbstract
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, IGF 1 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.
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- Authors
- Schirripa, M., Zhang, W., Heinemann, V., Cao, S., Okazaki, S., Yang, D., Loupakis, F., Berger, M. D., Ning, Y., Miyamoto, Y., Suenaga, M., Gopez, R. F., West, J. D., Hanna, D., Barzi, A., Falcone, A., Stintzing, S., & Lenz, H.
- Affiliations
- University of Southern California (US)
- LMU Klinikum (DE)
- Istituto Oncologico Veneto (IT)
- Azienda Ospedaliera Universitaria Pisana (IT)
- Corresponding author
- Lenz, Heinz‐Josef
- ORCID
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2017-05-10
- Volume
- 141
- Issue
- 2
- Pages
- 383-392
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- PMC
- PMC5510747
- OpenAlex
- W2604749288
- Cited by
- 11
- References
- 45
- Citations by year
- 2025: 1 · 2023: 2 · 2022: 4 · 2021: 2 · 2019: 2
- FWCI
- 0.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Funders
- National Cancer Institute (P30CA014089)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- single nucleotide polymorphisms, IRS-1, insulin receptor substrate 2, insulin-like growth factor I, IGF-1 receptor, metastatic colorectal cancer, FIRE-3 trial, prognostic factors, predictive biomarkers, RAS status, progression-free survival, overall survival
- MeSH terms
- Bevacizumab, Cetuximab, Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Leucovorin, Female, Fluorouracil, Humans, Male, Neoplasm Metastasis, Prognosis, Somatomedins, Colorectal Neoplasms, Signal Transduction, Survival Analysis, Sequence Analysis, DNA, Polymorphism, Single Nucleotide, Insulin Receptor Substrate Proteins, Genetic Association Studies
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