A Multi-Source Data Fusion Framework for Revealing the Regulatory Mechanism of Breast Cancer Immune Evasion

Abstract

For precision medicine, there is an enormous need to understand the immune evasion mechanism of tumor development, especially when tumor heterogeneity significantly affects the effect of immunotherapy. Recognizing the subtypes of breast cancer based on the immune-related genes helps to understand the immune escape pathways dominated by different subtypes, so as to implement effective treatment measures for different subtypes. For that, we used non-negative matrix factorization and consistent clustering algorithm on The Cancer Genome Atlas RNA-seq breast cancer data and recognized 4 subtypes according to the curated immune-related genes. Then, we conducted differential expression analysis between each subtype of breast cancer and normal tissue of RNA-seq data from non-cancer individuals collected by the Genotype-Tissue Expression to find out subtype-related immune genes. After that, we carried out correlation analysis between copy number variants (CNV) and mRNA of immune genes and investigated the regulatory mechanism of the immune genes, which cannot be explained by CNV based on ATAC-seq data. The experimental results reveal that CDH1 and PVRL2 are potential for immune evasion in all 4 subgroups. The expression variations of CDH1 can be mainly explained by its CNV, while the expression variation of PVRL2 is more likely regulated by transcript factors.

Characterization and clinical relevance of PDGFRA pathway copy number variation gains across human cancers

“…Furthermore, the relationship between CNVs and gene expression is crucial for the prevention, diagnosis, and treatment of cancer (Shao et al 2019 ). CNV-caused genetic mutations may lead to the development of immune escape (Chen et al 2020 ). It has also been reported that copy number gains (CN gain) occur more frequently than copy number losses (CN loss) during epithelial-mesenchymal transition (EMT), and somatic CN gain activates gene expression by increasing gene dosage (Zhao et al 2016 ).…”

Pan-cancer analyses and molecular subtypes based on the cancer-associated fibroblast landscape and tumor microenvironment infiltration characterization reveal clinical outcome and immunotherapy response in epithelial ovarian cancer

“…CNVs are an important form of genetic structural variation and are crucial for cancer diagnosis, prevention, and treatment. Furthermore, CNV-induced gene mutations may lead to immune escape ( 44 , 45 ). In our study, we observed a high CNV frequency in CAF markers and a correlation between CNV and marker expression, suggesting that CNV may affect CAF function and contribute to tumorigenesis.…”

The Single-Cell Sequencing: A Dazzling Light Shining on the Dark Corner of Cancer

“…ATAC-seq data have demonstrated that CDH1 is positively regulated by TFs such as NFATC2, XBP1, YY1AR, GTF2I, IRF2, and NF1, and variations in CDH1 expression are mainly caused by CNV. However, CNV and the mRNA level of PVRL2 are very weakly correlated, and high expression of PVRL2 may also be induced by increases in TFs including FOXP3, GTF2I, YY1, NR3C1, SP1, TFAP2A, AR, ESR1, PAX5, and TP53 ( 80 ). This evidence indicates that ITH in breast cancer is boosted by the combined action of tumor cells and immune cells in the TME.…”