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Inflammatory gene profiling of Ewing sarcoma family of tumors (set A)

ABSTRACT: Purpose: Unlike in most adult-onset cancers, an association between typical paediatric neoplasms and inflammatory triggers is rare. We studied whether immune system related genes are activated and have prognostic significance in Ewing sarcoma family of tumours (ESFT). Experimental design: Data-analysis was performed on gene expression profiles of 44 ESFT patient, 11 ESFT cell line, and 18 normal muscle tissue samples. 238 inflammation related genes were selected based on literature and a macrophage gene expression signature was derived from SymAtlas. Differential expression of the genes was analysed by t-test and survival analysis was performed according to gene expression. Results: Inflammatory genes are activated in ESFT patient samples, as 38 of 238 (16%) inflammatory genes were significantly upregulated (p<0.001) when compared to ESFT cell lines. This inflammatory gene activation was characterized by significant enrichment of macrophage related gene expression with 58 of 299 (19%) of these genes being upregulated (p<0.001). By combining expression data from ESFT patients, cell lines and muscle tissue samples we were able to identify a total of 32 presumptive inflammatory genes that characterize and distinguish tumour site in vivo from surrounding normal tissues. High expression of C5 correlated with better event free (p=0.01) and overall survival (p=0.004) in dose dependent manner. C5 and its receptor C5aR1 expression was verified at protein level by immunohistochemistry on tumor tissue microarray. Also, high expression of JAK1 correlated with favourable overall survival (p=0.04) and high expression of IL8, derived presumably from infiltrating immune cells, resulted in poor overall survival in Ewing sarcoma (p=0.04). Conclusions: Immune system related gene activation is observed in ESFT patient samples and several prognostically significant inflammatory genes (C5, JAK1 and IL8) for ESFT were identified.

ORGANISM(S): Homo sapiens

PROVIDER: GSE17618 | GEO | 2011/12/01

SECONDARY ACCESSION(S): PRJNA123367

REPOSITORIES: GEO

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Project description:Purpose: Unlike in most adult-onset cancers, an association between typical paediatric neoplasms and inflammatory triggers is rare. We studied whether immune system related genes are activated and have prognostic significance in Ewing sarcoma family of tumours (ESFT). Experimental design: Data-analysis was performed on gene expression profiles of 44 ESFT patient, 11 ESFT cell line, and 18 normal muscle tissue samples. 238 inflammation related genes were selected based on literature and a macrophage gene expression signature was derived from SymAtlas. Differential expression of the genes was analysed by t-test and survival analysis was performed according to gene expression. Results: Inflammatory genes are activated in ESFT patient samples, as 38 of 238 (16%) inflammatory genes were significantly upregulated (p<0.001) when compared to ESFT cell lines. This inflammatory gene activation was characterized by significant enrichment of macrophage related gene expression with 58 of 299 (19%) of these genes being upregulated (p<0.001). By combining expression data from ESFT patients, cell lines and muscle tissue samples we were able to identify a total of 32 presumptive inflammatory genes that characterize and distinguish tumour site in vivo from surrounding normal tissues. High expression of C5 correlated with better event free (p=0.01) and overall survival (p=0.004) in dose dependent manner. C5 and its receptor C5aR1 expression was verified at protein level by immunohistochemistry on tumor tissue microarray. Also, high expression of JAK1 correlated with favourable overall survival (p=0.04) and high expression of IL8, derived presumably from infiltrating immune cells, resulted in poor overall survival in Ewing sarcoma (p=0.04). Conclusions: Immune system related gene activation is observed in ESFT patient samples and several prognostically significant inflammatory genes (C5, JAK1 and IL8) for ESFT were identified. 44 Ewing sarcoma family of tumor patient and 11 cell line samples were analysed for their gene expression.

Project description:Purpose: Unlike in most adult-onset cancers, an association between typical paediatric neoplasms and inflammatory triggers is rare. We studied whether immune system related genes are activated and have prognostic significance in Ewing sarcoma family of tumours (ESFT). Experimental design: Data-analysis was performed on gene expression profiles of 44 ESFT patient, 11 ESFT cell line, and 18 normal muscle tissue samples. 238 inflammation related genes were selected based on literature and a macrophage gene expression signature was derived from SymAtlas. Differential expression of the genes was analysed by t-test and survival analysis was performed according to gene expression. Results: Inflammatory genes are activated in ESFT patient samples, as 38 of 238 (16%) inflammatory genes were significantly upregulated (p<0.001) when compared to ESFT cell lines. This inflammatory gene activation was characterized by significant enrichment of macrophage related gene expression with 58 of 299 (19%) of these genes being upregulated (p<0.001). By combining expression data from ESFT patients, cell lines and muscle tissue samples we were able to identify a total of 32 presumptive inflammatory genes that characterize and distinguish tumour site in vivo from surrounding normal tissues. High expression of C5 correlated with better event free (p=0.01) and overall survival (p=0.004) in dose dependent manner. C5 and its receptor C5aR1 expression was verified at protein level by immunohistochemistry on tumor tissue microarray. Also, high expression of JAK1 correlated with favourable overall survival (p=0.04) and high expression of IL8, derived presumably from infiltrating immune cells, resulted in poor overall survival in Ewing sarcoma (p=0.04). Conclusions: Immune system related gene activation is observed in ESFT patient samples and several prognostically significant inflammatory genes (C5, JAK1 and IL8) for ESFT were identified. 44 Ewing sarcoma family of tumor patient and 18 normal muscle samples obtained from GSE6798 and GSE3526.

Project description:EWS-FLI1 is a chimeric ETS transcription factor that is, due to a chromosomal rearrangement, specifically expressed in Ewing’s sarcoma family tumors (ESFT) and is thought to be the initiating event in the development of the disease. Previous genomic profiling experiments have identified a number of EWS-FLI1 regulated genes and genes that discriminate ESFT from other sarcomas, but so far a comprehensive analysis of EWS-FLI1 dependent molecular functions characterizing this aggressive cancer is lacking. In this study a molecular function map of ESFT was constructed based on an integrative analysis of gene expression profiling experiments on a uniform microarray platform following EWS-FLI1 knockdown in a panel of five ESFT cell lines, and on gene expression data from the same platform of 59 primary ESFT tumors. Based on the assumption that EWS-FLI1 is the driving transcriptional force in ESFT pathogenesis, we predicted an inverse correlation of gene expression for EWS-FLI1 regulated genes between the putative tissue of origin and the cell lines under EWS-FLI1 knockdown conditions. Consistent with recent reports, mesenchymal progenitor cells (MPC) were found to fit this hypothesis best and were therefore used as the reference tissue for the construction of the molecular function map in ESFT. The interrelations of molecular pathways were visualized by measuring the similarity among annotated gene functions by gene sharing. The molecular function map highlighted distinct clusters of activities for EWS-FLI1 regulated genes in ESFT and revealed a striking difference between EWS-FLI1 up- and down-regulated genes: EWS-FLI1 induced genes mainly belong to cell cycle regulation, proliferation and response to DNA damage, while repressed genes were associated with differentiation and cell communication. This study revealed that EWS-FLI1 combines by distinct molecular mechanisms two important functions of cellular transformation in one protein, growth promotion and differentiation blockage. By taking MPC as a reference tissue a significant EWS-FLI1 signature was discovered in ESFT that only partially overlapped with previously published EWS-FLI1 dependent gene expression patterns, identifying a series of novel targets for the chimeric protein in ESFT. Our results may guide target selection for future ESFT specific therapies. Keywords: Ewing's Sarcoma, EWS-FLI1, RNAi knock down and controls

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Inflammatory gene profiling of Ewing sarcoma family of tumors (set A)

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