Insulin-like growth factor 2 hypermethylation in peripheral blood leukocytes and colorectal cancer risk and prognosis: a propensity score analysis of multiple-centre populations

ABSTRACT Background To comprehensively assess and validate the associations between insulin-like growth factor 2 ( IGF2 ) gene methylation in peripheral blood leukocytes (PBLs) and colorectal cancer (CRC) risk and prognosis. Methods The association between IGF2 methylation in PBLs and CRC risk was initially evaluated in a case-control study and then validated in a nested case-control study and a twins’ case-control study, respectively. Meanwhile, an initial CRC patient cohort was used to assess the effect of IGF2 methylation on CRC prognosis and then the finding was validated in the EPIC-Italy CRC cohort and TCGA datasets. A propensity score (PS) analysis was performed to control for confounders, and extensive sensitivity analyses were performed to assess the robustness of our findings. Results PBL IGF2 hypermethylation was associated with an increased risk of CRC in the initial study (OR PS-adjusted , 2.57, 95% CI: 1.65 to 4.03, P <0.0001), and this association was validated using two independent external datasets (OR PS-adjusted , 2.21, 95% CI: 1.28 to 3.81, P =0.0042 and OR PS-adjusted , 10.65, 95% CI: 1.26 to 89.71, P =0.0295, respectively). CRC patients with IGF2 hypermethylation in PBLs had significantly improved overall survival compared to those patients with IGF2 hypomethylation (HR PS-adjusted , 0.47, 95% CI: 0.29 to 0.76, P =0.0019). The prognostic signature was also observed in the EPIC-Italy CRC cohort, although the HR did not reach statistical significance (HR PS-adjusted , 0.69, 95% CI: 0.37 to 1.27, P =0.2359). Conclusions IGF2 hypermethylation may serve as a potential blood-based predictive biomarker for the identification of individuals at high risk of developing CRC and for CRC prognosis. Funding This work was supported by the China Postdoctoral Science Foundation (grant number 2018M641875 to YPL); the Natural Science Foundation of Heilongjiang Province (grant number YQ2019H021 to YPL); the National Natural Science Foundation of China (grant number 81473055 to YSZ), and by grant from the SCORE Foundation (Y-MX2016-045 to YLL). Clinical trial number Not applicable.