Pan-cancer analyses of senescence-related genes in extracellular matrix characterization in cancer

Abstract

Abstract Purpose The aged microenvironment plays a crucial role in tumor onset and progression. However, it remains unclear whether and how the aging of the extracellular matrix (ECM) influences cancer onset and progression. Furthermore, the mechanisms and implications of extracellular matrix senescence-related genes (ECM-SRGs) in pan-cancer have not been investigated. Methods We collected profiling data from over 10,000 individuals, covering 33 cancer types, 750 small molecule drugs, and 24 immune cell types, for a thorough and systematic analysis of ECM-SRGs in cancer. Results We observed a significant correlation between immune cell infiltrates and Gene Set Variation Analysis enrichment scores of ECM-SRGs in 33 cancer types. Moreover, our results revealed significant differences in immune cell infiltration among patients with copy number variations (CNV) and single nucleotide variations (SNV) in ECM-SRGs across various malignancies. Aberrant hypomethylation led to increased ECM-SRGs expression, and in specific malignancies, a connection between ECM-SRGs hypomethylation and adverse patient survival was established. The frequency of CNV and SNV in ECM-SRGs was elevated. We observed a positive correlation between CNV, SNV, and ECM-SRGs expression. Furthermore, a correlation was found between the high frequency of CNV and SNV in ECM-SRGs and poor patient survival in several cancer types. Additionally, the results demonstrated that ECM-SRGs expression could serve as a predictor of patient survival in diverse cancers. Pathway analysis unveiled the role of ECM-SRGs in activating EMT, apoptosis, and the RAS/MAPK signaling pathway while suppressing the cell cycle, hormone AR, and the response to DNA damage signaling pathway. Finally, we conducted searches in the “Genomics of Drug Sensitivity in Cancer” and “Genomics of Therapeutics Response Portal” databases, identifying several drugs that target ECM-SRGs. Conclusions We conducted a comprehensive evaluation of the genomes and immunogenomics of ECM-SRGs, along with their clinical features in 33 solid tumors. This may provide insights into the relationship between ECM-SRGs and tumorigenesis. Consequently, targeting these ECM-SRGs holds promise as a clinical approach for cancer treatment.