Single nucleotide polymorphisms in the IGF-IRS pathway are associated with outcome in mCRC patients enrolled in the FIRE-3 trial

Schirripa, Marta; Zhang-Wu, Xiaxia; Heinemann, Volker; Cao, Shu; Okazaki, Satoshi; Yang, Dongyun; Loupakis, Fotios; Berger, Martin Dave; Ning, Yan; Miyamoto, Yuji; Suenaga, Mitsukuni; Gopez, Roel F; West, Jordan D; Hanna, Diana; Barzi, Afsaneh; Falcone, Alfredo; Stintzing, Sebastian; Lenz, Heinz-Josef (2017). Single nucleotide polymorphisms in the IGF-IRS pathway are associated with outcome in mCRC patients enrolled in the FIRE-3 trial. International journal of cancer, 141(2), pp. 383-392. Wiley-Blackwell 10.1002/ijc.30715

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Berger, Martin Dave

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0020-7136

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Nicole Corminboeuf

Date Deposited:

28 Mar 2018 13:07

Last Modified:

03 Nov 2019 08:59

Publisher DOI:

10.1002/ijc.30715

PubMed ID:

28369940

Uncontrolled Keywords:

IGF IRS RAS SNP metastatic colorectal cancer

BORIS DOI:

10.7892/boris.111408

URI:

https://boris.unibe.ch/id/eprint/111408

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