DNA hypomethylation patterns and their impact on the tumor microenvironment in colorectal cancer

作者：He Huang, Qian Li, Xusheng Tu, Dongyue Yu, Yundong Zhou, Lifei Ma, Kongyuan Wei, Yuzhen Gao, Guodong Zhao, Ruiqin Han, Fangdie Ye, Chunlian Ke · 发表于：Cellular Oncology · 年份：2024 · DOI：10.1007/s13402-024-00933-x · 被引用次数：12 · 研究领域：Ferroptosis and cancer prognosis、Epigenetics and DNA Methylation、Cancer Immunotherapy and Biomarkers

BACKGROUND: Recent research underscores the pivotal role of immune checkpoints as biomarkers in colorectal cancer (CRC) therapy, highlighting the dynamics of resistance and response to immune checkpoint inhibitors. The impact of epigenetic alterations in CRC, particularly in relation to immune therapy resistance, is not fully understood. METHODS: We integrated a comprehensive dataset encompassing TCGA-COAD, TCGA-READ, and multiple GEO series (GSE14333, GSE37892, GSE41258), along with key epigenetic datasets (TCGA-COAD, TCGA-READ, GSE77718). Hierarchical clustering, based on Euclidean distance and Ward's method, was applied to 330 primary tumor samples to identify distinct clusters. The immune microenvironment was assessed using MCPcounter. Machine learning algorithms were employed to predict DNA methylation patterns and their functional enrichment, in addition to transcriptome expression analysis. Genomic mutation profiles and treatment response assessments were also conducted. RESULTS: Our analysis delineated a specific tumor cluster with CpG Island (CGI) methylation, termed the Demethylated Phenotype (DMP). DMP was associated with metabolic pathways such as oxidative phosphorylation, implicating increased ATP production efficiency in mitochondria, which contributes to tumor aggressiveness. Furthermore, DMP showed activation of the Myc target pathway, known for tumor immune suppression, and exhibited downregulation in key immune-related pathways, suggesting a tumor microenvi...