Background: The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is involved in a series of biological processes. Aberrant promoter methylation of CpG islands plays an important role in carcinogenesis. However, the association between the DNA methylation of JAK-STAT pathway-related genes in peripheral blood leukocytes and colorectal cancer (CRC) susceptibility remains unclear. Methods: We conducted a case-control study of 403 patients with CRC and 419 cancer free

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... controls, and the DNA methylation levels of four genes (JAK2, STAT1, STAT3, and SOCS3) in peripheral blood samples from all subjects were assessed using a methylation-sensitive high-resolution melting (MS-HRM) analysis. Results: Compared with controls, the methylation of the JAK2, STAT1 and SOCS3 genes significantly increased the CRC risk (ORadjusted=1.96, 95% CI, 1.12-3.41, P=0.01; ORadjusted=5.37, 95% CI, 3.74-7.71, P<0.01; ORadjusted=3.30, 95% CI, 1.58-6.87, P<0.01, respectively). This trend was also found via stratified analysis. In the multiple CpG site methylation (MCSM) analysis, a high MCSM value denoted a significantly increased risk of CRC (ORadjusted=4.97, 95% CI, 3.34-7.37, P<0.01). Antagonistic interactions were identified between the methylation of JAK2, STAT1 and high levels of MCSM and environmental factors with CRC risk (P<0.05). Conclusion: In peripheral blood, the methylation statuses of JAK2, STAT1, and high levels of MCSM, which are promising biomarkers, were significantly associated with CRC risk. An interaction between gene methylation and environmental factors contributed to the risk of CRC.