BackgroundThe receptors, ligands, and associated proteins of the insulin-like growth factor (IGF) family are involved in cancer development. TheIGF1receptor and its accompanying signaling cascade are a crucial growth-regulatory mechanism that plays an important role in colorectal cancer (CRC) proliferation and differentiation.IRS1(Insulin receptor substrate-1), a major substrate for theIGF1R, is involved in cell growth and promotes tumorigenesis. There are shreds of evidence from prior research suggesting thatIGFsystem polymorphisms may influence susceptibility to CRC. However, the findings in this area were contradictory. Accordingly, we carried out a systematic literature search to identify all case-control, cross-sectional, and cohort studies on the association between various polymorphisms across fourIGF1pathway genes (IGF1,IGF1R,IRS1, andIRS2) and the risk of CRC.MethodsWe performed a comprehensive search strategy in PubMed, Scopus, and Web of Science databases for articles available until Aug 30, 2022. A total of 26 eligible studies withIGF1/IGF1R,IRS1andIRS2polymorphisms; met the inclusion criteria. All case-control studies forIGF1rs6214C>T,IRS1rs1801278G>A, andIRS2rs1805097G>A comprising 22,084 cases and 29,212 controls were included in the current meta-analysis. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate relationships between the polymorphisms and CRC susceptibility. All statistical analyses were performed using STATA software version 14.0.ResultsThe meta-analysis of available data for rs6214C>T, rs1801278G>A, and rs1805097G>A showed a significant association between these polymorphisms and an increased CRC risk in some of the comparisons studied (rs6214C>T, pooled OR for CC = 0.43, 95% CI 0.21- 0.87, P = 0.019; rs1801278G>A, OR for GA = 0.74, 95% CI 0.58-0.94, P = 0.016; rs1805097G>A, OR for GA = 0.83, 95% CI 0.71-0.96, P = 0.013). Nevertheless, the meta-analysis did not include other genetic variations inIGF1, IGF1R, IRS1, andIRS2due to heterogeneity and limited sample size.ConclusionsThis systematic review and meta-analysis provide evidence that genetic variants inIGF1rs6214C>T,IRS1rs1801278G>A, andIRS2rs1805097G>A are associated with an increased risk of CRC. These findings may contribute to a better understanding of the complex genetic mechanisms involved in CRC development and could inform future research on prevention and treatment strategies for this disease.