Prognostic and therapeutic implications of extracellular matrix associated gene signature in renal clear cell carcinoma

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 cle...

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Autores principales:	Pankaj Ahluwalia, Meenakshi Ahluwalia, Ashis K. Mondal, Nikhil Sahajpal, Vamsi Kota, Mumtaz V. Rojiani, Amyn M. Rojiani, Ravindra Kolhe
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f621f9d36b0a43ddb286cec1169bbb0b
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spelling	oai:doaj.org-article:f621f9d36b0a43ddb286cec1169bbb0b2021-12-02T18:15:25ZPrognostic and therapeutic implications of extracellular matrix associated gene signature in renal clear cell carcinoma10.1038/s41598-021-86888-72045-2322https://doaj.org/article/f621f9d36b0a43ddb286cec1169bbb0b2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86888-7https://doaj.org/toc/2045-2322Abstract 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.Pankaj AhluwaliaMeenakshi AhluwaliaAshis K. MondalNikhil SahajpalVamsi KotaMumtaz V. RojianiAmyn M. RojianiRavindra KolheNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Pankaj Ahluwalia Meenakshi Ahluwalia Ashis K. Mondal Nikhil Sahajpal Vamsi Kota Mumtaz V. Rojiani Amyn M. Rojiani Ravindra Kolhe Prognostic and therapeutic implications of extracellular matrix associated gene signature in renal clear cell carcinoma
description	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.
format	article
author	Pankaj Ahluwalia Meenakshi Ahluwalia Ashis K. Mondal Nikhil Sahajpal Vamsi Kota Mumtaz V. Rojiani Amyn M. Rojiani Ravindra Kolhe
author_facet	Pankaj Ahluwalia Meenakshi Ahluwalia Ashis K. Mondal Nikhil Sahajpal Vamsi Kota Mumtaz V. Rojiani Amyn M. Rojiani Ravindra Kolhe
author_sort	Pankaj Ahluwalia
title	Prognostic and therapeutic implications of extracellular matrix associated gene signature in renal clear cell carcinoma
title_short	Prognostic and therapeutic implications of extracellular matrix associated gene signature in renal clear cell carcinoma
title_full	Prognostic and therapeutic implications of extracellular matrix associated gene signature in renal clear cell carcinoma
title_fullStr	Prognostic and therapeutic implications of extracellular matrix associated gene signature in renal clear cell carcinoma
title_full_unstemmed	Prognostic and therapeutic implications of extracellular matrix associated gene signature in renal clear cell carcinoma
title_sort	prognostic and therapeutic implications of extracellular matrix associated gene signature in renal clear cell carcinoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f621f9d36b0a43ddb286cec1169bbb0b
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Prognostic and therapeutic implications of extracellular matrix associated gene signature in renal clear cell carcinoma

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