Abstract
Complex interactions in tumor microenvironment between ECM (extra-cellular matrix) and cancer cell plays a central role in the generation of tumor supportive microenvironment. In this study, the expression of ECM-related genes was explored for prognostic and immunological implication in clear cell renal clear cell carcinoma (ccRCC). Out of 964 ECM genes, higher expression (z-score > 2) of 35 genes showed significant association with overall survival (OS), progression-free survival (PFS) and disease-specific survival (DSS). On comparison to normal tissue, 12 genes (NUDT1, SIGLEC1, LRP1, LOXL2, SERPINE1, PLOD3, ZP3, RARRES2, TGM2, COL3A1, ANXA4, and POSTN) showed elevated expression in kidney tumor (n = 523) compared to normal (n = 100). Further, Cox proportional hazard model was utilized to develop 12 genes ECM signature that showed significant association with overall survival in TCGA dataset (HR = 2.45; 95% CI [1.78–3.38]; p < 0.01). This gene signature was further validated in 3 independent datasets from GEO database. Kaplan–Meier log-rank test significantly associated patients with elevated expression of this gene signature with a higher risk of mortality. Further, differential gene expression analysis using DESeq2 and principal component analysis (PCA) identified genes with the highest fold change forming distinct clusters between ECM-rich high-risk and ECM-poor low-risk patients. Geneset enrichment analysis (GSEA) identified significant perturbations in homeostatic kidney functions in the high-risk group. Further, higher infiltration of immunosuppressive T-reg and M2 macrophages was observed in high-risk group patients. The present study has identified a prognostic signature with associated tumor-promoting immune niche with clinical utility in ccRCC. Further exploration of ECM dynamics and validation of this gene signature can assist in design and application of novel therapeutic approaches.
Highlights
Complex interactions in tumor microenvironment between Extracellular matrix (ECM) and cancer cell plays a central role in the generation of tumor supportive microenvironment
We developed a 12-gene ECM gene prognostic signature based on The Cancer Genome Atlas (TCGA) dataset and validated it in 3 independent Gene Expression Omnibus (GEO) datasets
These results suggest that the 12-gene ECM signature can be used for prognosis as well as identify patients with suppressive immune phenotypes which can benefit from emerging therapies under research such as T-reg depletion immunotherapies
Summary
Complex interactions in tumor microenvironment between ECM (extra-cellular matrix) and cancer cell plays a central role in the generation of tumor supportive microenvironment. Cox proportional hazard model was utilized to develop 12 genes ECM signature that showed significant association with overall survival in TCGA dataset (HR = 2.45; 95% CI [1.78–3.38]; p < 0.01) This gene signature was further validated in 3 independent datasets from GEO database. We developed a 12-gene ECM gene prognostic signature based on TCGA dataset and validated it in 3 independent GEO datasets These genes had significantly higher expression levels in RCC tumor compared to normal tissue. The patients with high ECM signature showed a higher fraction of tumor-promoting T regulatory and M2 macrophages These results suggest that the 12-gene ECM signature can be used for prognosis as well as identify patients with suppressive immune phenotypes which can benefit from emerging therapies under research such as T-reg depletion immunotherapies
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