Methylation of Immune-Related Genes in Peripheral Blood Leukocytes and Breast Cancer.

Tian Tian,Hongru Sun,Yashuang Zhao,Xianyu Zhang,Ding Zhang,Ting Zheng,Da Pang,Xuan Wang,Jinming Fu,Yupeng Liu,Dapeng Li

doi:10.3389/fonc.2022.817565

Abstract

Abnormal DNA methylation contributes to breast cancer (BC). Immune-related genes play crucial roles in BC development and progression. This study aims to investigate the effect of methylation of immune-related genes in peripheral blood leukocytes (PBLs) on BC risk. GSE51032 and GSE104942 datasets were used to identify significantly differentially methylated CpG sites (DMCs) of immune-related genes. A case-control study was conducted using MethylTarget sequencing to validate the relationship between the methylation levels of the screened genes and BC risk. We also evaluated the association between methylation haplotypes of screened genes and BC risk. Moreover, we sorted the blood leukocytes into T cells, B cells, and monocytes to detect the difference of DNA methylation in different cell subtypes. A total of five DMCs were screened from GEO datasets, including cg01760846 (PSMC1), cg07141527 (SPPL3), cg15658543 (CARD11), cg21568368 (PSMB8), and cg24045276 (NCF2). In the case-control study, there were significant associations between methylation of the CpG sites in the five genes and BC risk. Methylation haplotype burdens of PSMC1, CARD11, and PSMB8 were associated with reduced BC risk. Moreover, there were heterogeneities in the methylation levels of the genes in different cell subtypes. In conclusion, methylation of PSMC1, SPPL3, CARD11, PSMB8, and NCF2 in PBLs were associated with BC risk. The five-gene methylation could be the potential biomarkers for predicting BC risk.

Highlights

Breast cancer (BC) is one of the most common malignant tumors in women worldwide, accounting for an estimated 2,261,419 new cases and 684,996 cancer deaths in 2020 [1]
We firstly screened the differentially methylated CpG sites (DMCs) of immune-related genes that related to breast cancer (BC) in peripheral blood leukocytes (PBLs) from the GEO public database
The differences in the methylation levels of five immune-related genes in T cells, B cells, and monocytes were analyzed by sorting PBLs

Summary

Introduction

Breast cancer (BC) is one of the most common malignant tumors in women worldwide, accounting for an estimated 2,261,419 new cases and 684,996 cancer deaths in 2020 [1]. In China, BC ranks first in terms of incidence and fifth in terms of mortality in women, with an increasing trend in both incidence and mortality [2]. Accumulating evidence proves that the occurrence and progression of BC result from environmental factors and genetic and epigenetic alterations [3]. DNA methylation, as one of the essential epigenetic modifications, has an important impact on normal cell physiology [4, 5]. Changes in DNA methylation involve focal hypermethylation and global hypomethylation.

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