抑制性免疫检查点 PDCD-1 和 LAG-3 高甲基化可能降低结直肠癌风险。

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

机构信息

Department of Epidemiology, Public Health College of Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang, People's Republic of China.

Department of Colorectal Cancer Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Nangang District, Harbin, 150001, Heilongjiang, People's Republic of China.

出版信息

Mol Med. 2021 Sep 20;27(1):114. doi: 10.1186/s10020-021-00373-5.

DOI:10.1186/s10020-021-00373-5

PMID:34544358

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8454079/

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 (OR = 0.322, 95% CI 0.197-0.528; OR = 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 (OR = 0.448, 95% CI 0.322-0.622; OR = 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.

摘要

背景

免疫检查点的 DNA 甲基化变化可能会影响其表达，进而影响肿瘤细胞的抗原加工和呈递，从而逃避免疫监视，导致结直肠癌（CRC）。本研究旨在探讨外周血白细胞中 PDCD-1、LAG-3 甲基化状态对 CRC 风险的影响。

方法

使用来自基因表达综合数据库（GEO）的 GSE51032 数据集，该数据集包含 166 例 CRC 患者和 424 例正常样本，以鉴定这两个基因的差异甲基化 CpG 位点。进行了一项病例对照研究，纳入 390 例 CRC 患者和 397 例无癌对照，以验证这两个基因的甲基化水平与 CRC 易感性之间的关系，并估计它们与环境因素对 CRC 风险的相互作用。

结果

在 GSE51032 数据集中，筛选出 cg06291111（PDCD-1）和 cg10191002（LAG-3）作为进一步研究的候选 CpG 位点。PDCD-1 和 LAG-3 的高甲基化与 CRC 风险降低显著相关（OR=0.322，95%CI 0.197-0.528；OR=0.666，95%CI 0.446-0.5996）。此外，病例对照研究的结果也显示出相似的趋势，即 PDCD-1 和 LAG-3 的高甲基化与 CRC 风险降低相关（OR=0.448，95%CI 0.322-0.622；OR=0.417，95%CI 0.301-0.578）。观察到 LAG-3 高甲基化与鸡蛋摄入对 CRC 风险的协同交互作用。PDCD-1 和 LAG-3 的高甲基化与环境因素对 CRC 风险存在联合作用。