Deciphering the nexus between the tumor immune microenvironment and DNA methylation in subgrouping estrogen receptor-positive breast cancer.

Abstract

Based on variable DNA methylation (DNAm), estrogen receptor (ER)-positive breast cancer (BRCA) is composed of two major subtypes, with the hypomethylated subgroup displaying good survival. Evidence indicates that the tumor microenvironment (TME) plays an important role in tumor progression and metastasis; however, its role and biological characteristics in DNAm-based subtypes of ER-positive BRCA remain largely unknown. Transcriptome data and matched clinical information of BRCA were downloaded from the Cancer Genome Atlas. Immune (ISs) and stromal scores (SSs) of BRCA patients were calculated using the ESTIMATE algorithm. Inferred fractions of 22 types of infiltrating immune cells of BRCA were collected from the Cancer Immunome Atlas. The hypomethylated ER-positive BRCA subtype displayed high ISs, echoing the finding that higher ISs are associated with good BRCA survival. In addition, we analyzed the differentially expressed genes between the hypo-high-IS and hyper-low-IS BRCA subtypes in ER-positive patients and identified a co-expressed gene module (i.e., red module) enriched in immune-related biological processes (e.g., leukocyte activation involved in immune response). Moreover, four hub genes (i.e., PLEK, CD53, EVI2B, and CD4) in this module showed significant association between their expression and ER-positive BRCA survival. We found differences in the tumor immune microenvironment (TIME) between DNAm-based BRCA subgroups in ER-positive patients and identified a specific module and hub genes involved to these differences. These findings elucidate the immunological basis for ER-positive BRCA progression and classification and provide potential gene biomarkers and targets for ER-positive BRCA diagnosis and treatment.