Inhibitory immune checkpoints PDCD-1 and LAG-3 hypermethylation may reduce the risk of colorectal cancer.

ABSTRACT

BACKGROUND: Changes in DNA methylation of immunosuppressive checkpoints may impact express and consequently affect antigen processing and presentation by tumor cells and facilitates evasion of immunosurveillance and lead to colorectal cancer (CRC). This study is to investigate the effect of PDCD-1, LAG-3 methylation statuses in peripheral blood leukocytes on CRC risk. METHODS: GSE51032 dataset from Gene Expression Omnibus comprised of 166 CRC patients and 424 normal samples was used to identify significantly differentially methylated CpG sites of the two genes. A case-control study with 390 CRC patients and 397 cancer-free controls was carried out to validate the relationship between the methylation levels of the two genes and CRC susceptibility and then estimated their interactions with environmental factors on CRC risk. RESULTS: In the GSE51032 dataset, cg06291111 (PDCD-1) and cg10191002 (LAG-3) were screened as the candidate CpG sites for the following study. There were significant associations between hypermethylation of PDCD-1 and LAG-3 and lower risk of CRC (ORadj = 0.322, 95% CI 0.197-0.528; ORadj = 0.666, 95% CI 0.446-0.5996, respectively). Moreover, the results in case-control study showed similar trend, that hypermethylation of PDCD-1 and LAG-3 were associated with lower CRC risk (ORadj = 0.448, 95% CI 0.322-0.622; ORadj = 0.417, 95% CI 0.301-0.578, respectively). A synergistic interaction between LAG-3 hypermethylation and intake of eggs on CRC risk was observed. There were combination effects between hypermethylation of PDCD-1 and LAG-3 and environmental factors on CRC risk. CONCLUSIONS: PDCD-1 and LAG-3 may potentially serve as blood-based predictive biomarkers for CRC risk.