A five‐gene signature is a prognostic biomarker in pan‐cancer and related with immunologically associated extracellular matrix

Abstract

The tumor microenvironment (TME) is related to extracellular matrix (ECM) dynamics and has a broad fundamental and mechanistic role in tumorigenesis and cancer progression. We hypothesized that ECM regulators might play an essential role in pan‐cancer attribution by causing a generic effect through its regulation of the dynamics of ECM alteration. By analyzing data from TCGA using GSEA and univariate Cox regression analysis, we found that ECM regulator genes were significantly enriched and contributed to mortality in various cancer types. Notably, UMAP analysis revealed that ECM regulator genes dominated the differences between tumor and adjacent normal tissues based on 59 or 31 pan‐survival‐related ECM gene sets. Subsequently, a five‐gene signature consisting of the predominant ECM regulators ADAM12, MMP1, SERPINE1, PLOD3, and P4HA3 was identified. We found that this five‐gene signature was pro‐mortality in 18 types of cancer in TCGA, and validated eleven other cancer types in TCGA and seven types in the TARGET and CoMMpass databases using overall survival analysis. KEGG pathway enrichment and Pearson correlation analysis indicated that these five component genes that were correlated with specific ECM proteins involved in tumorigenesis from the ECM receptor interaction gene set. Additionally, the fitted results of a linear model were applied to strengthen the discovery, demonstrating that the five genes were correlated with immune infiltration score and especially associated with typically immunologically “cold” tumors. We thus conclude that the ADAM12, MMP1, SERPINE1, PLOD3, and P4HA3 signature showed a close association with a pan‐cancer effect on prognosis and is related to ECM proteins in the TME which corresponding with immunologically “cold” cancer types.

Tumor mutational burden presents limiting effects on predicting the efficacy of immune checkpoint inhibitors and prognostic assessment in adrenocortical carcinoma

“…2 H). For instance, extracellular matrix (ECM) is the dynamic foundation of tumorigenesis and cancer progression [ 25 ]. The active assemblage of ECM undoubtedly contributes to cancer development.…”

ADAR2 Protein Is Associated with Overall Survival in GBM Patients and Its Decrease Triggers the Anchorage-Independent Cell Growth Signature

“…Using gene list enrichment analysis tools (i.e., Enrichr [ 30 ]), we found some shared molecular pathways belonging to specific cancer signatures, such as hypoxia, glycolysis, and epithelial–mesenchymal transition pathways, with the latter being the most representative one, with seven genes ( Figure 4 b). Interestingly, among the seven genes upregulated by ADAR2 in both of the GBM cell lines appeared ADAM12, MMP1, and SERPINE1, which were recently identified as key extracellular matrix (ECM) regulator genes in several cancer types [ 31 ]. Moreover, ADAM12 was previously identified among the ADAR2-edi-miR-589-3p-modulated genes [ 16 ].…”

Prediction of pan-solid tumor pembrolizumab benefit by integrating tumor mutation and gene expression profiling

“…Although less is known about the direct role of ADAM12 in CPI response, it is highly expressed by cancer associated fibroblasts CAFs-as shown through single cell sequencing studies and bulk tumor profilingas a driver of feed forward TGF-β signaling, has been shown to act as a T cell co-stimulatory molecule expressed on some regulatory T cells, and has been identified in a signature of negative response to ICI in melanoma [52][53][54][55][56][57] . Of note, in colorectal cancer, where single cell sequencing demonstrated high ADAM12 expression in CAFs 58 , as well as urothelial carcinoma, TGF-β signaling from CAFs has been shown to drive T cell exclusion, a hallmark of low response to ICI [59][60][61][62][63] .…”