Prognostic significance of interferon-γ and its signaling pathway in early breast cancer depends on the molecular subtypes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE158309 | GEO | 2020/09/22
REPOSITORIES: GEO
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Project description:There are no widely-accepted prognostic markers currently available to predict outcomes in patients with triple-negative breast cancer (TNBC), and no targeted therapies with confirmed benefit. We have used MALDI mass spectrometry imaging (MSI) of tryptic peptides to compare regions of cancer and benign tissue in 10 formalin-fixed, paraffin-embedded sections of TNBC tumors. Proteins were identified by reference to a peptide library constructed by LC-MALDI-MS/MS analyses of the same tissues. The prognostic significance of proteins that distinguished between cancer and benign regions was estimated by Kaplan-Meier analysis of their gene expression from public databases. Among peptides that distinguished between cancer and benign tissue in at least 3 tissues with a ROC area under the curve >0.7, 14 represented proteins identified from the reference library, including proteins not previously associated with breast cancer. Initial network analysis using the STRING database showed no obvious functional relationships except among collagen subunits COL1A1, COL1A2, and COL63A, but manual curation, including the addition of EGFR to the analysis, revealed a unique network connecting 10 of the 14 proteins. Kaplan-Meier survival analysis to examine the relationship between tumor expression of genes encoding the 14 proteins, and recurrence-free survival (RFS) in patients with basal-like TNBC showed that, compared to low expression, high expression of nine of the genes was associated with significantly worse RFS, most with hazard ratios >2. In contrast, in estrogen receptor-positive tumors, high expression of these genes showed only low, or no, association with worse RFS. These proteins are proposed as putative markers of RFS in TNBC, and some may also be considered as possible targets for future therapies.
2019-05-06 | PXD013397 | Pride
Project description:PURPOSE: We sought to identify genes of clinical significance to predict survival and the risk for colorectal liver metastasis (CLM), the most common site of metastasis from colorectal cancer (CRC). PATIENTS AND METHODS: We profiled gene expression in 31 specimens from primary CRC and 32 unmatched specimens of CLM, and performed Significance Analysis of Microarrays (SAM) of the expressed genes between these two groups. To characterize the clinical relevance of two highly-ranked differentially expressed signature genes, we analyzed the expression of secreted phosphoprotein 1 (SPP1 or osteopontin) and lymphoid enhancer factor-1 (LEF1) by immunohistochemistry using a tissue microarray (TMA) representing an independent set of 154 patients with primary CRC. Supervised analysis using SAM identified 963 genes with significantly higher expression in CLM compared to primary CRC, with a false discovery rate of <0.5%. TMA analysis showed SPP1 and LEF1 protein overexpression in 60% and 44% of CRC cases, respectively. Subsequent occurrence of CLM was significantly correlated with the overexpression of LEF1 (chi-square p = 0.035), but not SPP1 (p = 0.14). Kaplan Meier analysis revealed significantly worse survival in patients with overexpression of LEF1 (p < 0.01), but not SPP1 (p = 0.11). Both univariate and multivariate analyses identified stage (p < 0.0001) and LEF1 overexpression (p < 0.05) as important prognostic markers, but not tumor grade or SPP1. CONCLUSION: Among signature genes differentially expressed between CLM and primary CRC, we demonstrate overexpression of LEF1 in primary CRC to be a prognostic factor for poor survival and increased risk for liver metastasis. cDNA microarrays from the Stanford Functional Genomics Facility were used to perform mRNA transcript profiling of 31 freshly-frozen primary colorectal cancer specimens, and compared to published profiles of 32 unmatched colorectal liver metastases and 12 normal liver specimens.
2011-03-22 | E-GEOD-22834 | biostudies-arrayexpress
Project description:PURPOSE: We sought to identify genes of clinical significance to predict survival and the risk for colorectal liver metastasis (CLM), the most common site of metastasis from colorectal cancer (CRC). PATIENTS AND METHODS: We profiled gene expression in 31 specimens from primary CRC and 32 unmatched specimens of CLM, and performed Significance Analysis of Microarrays (SAM) of the expressed genes between these two groups. To characterize the clinical relevance of two highly-ranked differentially expressed signature genes, we analyzed the expression of secreted phosphoprotein 1 (SPP1 or osteopontin) and lymphoid enhancer factor-1 (LEF1) by immunohistochemistry using a tissue microarray (TMA) representing an independent set of 154 patients with primary CRC. Supervised analysis using SAM identified 963 genes with significantly higher expression in CLM compared to primary CRC, with a false discovery rate of <0.5%. TMA analysis showed SPP1 and LEF1 protein overexpression in 60% and 44% of CRC cases, respectively. Subsequent occurrence of CLM was significantly correlated with the overexpression of LEF1 (chi-square p = 0.035), but not SPP1 (p = 0.14). Kaplan Meier analysis revealed significantly worse survival in patients with overexpression of LEF1 (p < 0.01), but not SPP1 (p = 0.11). Both univariate and multivariate analyses identified stage (p < 0.0001) and LEF1 overexpression (p < 0.05) as important prognostic markers, but not tumor grade or SPP1. CONCLUSION: Among signature genes differentially expressed between CLM and primary CRC, we demonstrate overexpression of LEF1 in primary CRC to be a prognostic factor for poor survival and increased risk for liver metastasis.
2011-03-22 | GSE22834 | GEO
Project description:Unbiased proteomics of human cerebrospinal fluid (CSF) has been used successfully to identify biomarkers of Amyotrophic Lateral Sclerosis (ALS). However, high abundance proteins mask the presence of lower abundance proteins that may hold valuable diagnostic and prognostic use. Developments in mass spectrometry proteomic data acquisition methods therefore hold promise for improved protein depth and more sensitive biomarker discovery. In this study, mass spectrometry with library-free data-independent acquisition (DIA) was used to compare the CSF proteome of 40 people with ALS, 15 healthy controls and 8 people with mimicking conditions. Qthen quantified protein groups were subsequently correlated with clinical variables. Univariate analysis identified 7 proteins significantly upregulated in ALS vs healthy controls, and 9 with altered abundance in ALS vs mimicking conditions (FDR <0.1). Elevated Chitotriosidase 1 (CHIT1) was common to both comparisons and showed strong correlation with disease progression rate (Pearson r =0.41, FDR-adjusted p = 0.035), but no association with survival (Pearson correlation and Kaplan-Meier survival analysis). Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1; upregulated in ALS vs healthy controls) showed a stronger correlation with disease progression rate (Pearson r = 0.53, FDR-adjusted p = 0.003) and significant association with survival in Kaplan Meier analysis (log rank p = 0.013) but no independent effect in proportional hazards models. Weighted correlation network analysis was then used to identify functionally relevant modules of proteins. One module, enriched for inflammatory functions, was strongly associated with age at disease onset (Pearson r = 0.58, FDR-adjusted p = 0.005) and survival (Hazard Ratio 1.78, FDR = 0.065), and a second module, enriched for endoplasmic reticulum proteins, negatively correlated with disease progression rate (r = -0.42, FDR-adjusted p =0.109). This study confirms that UCHL1 is strongly associated with disease progression and survival, and highlights potential of inflammatory and endoplasmic reticulum proteins to provide prognostic biomarker potential.
2024-05-21 | PXD044274 | Pride
Project description:STAG2 is targeted by somatic aberrations in a subset (4%) of human PDAs. Transposon mediated disruption of STAG2 in a KRASG12D genetically engineered mouse model promotes the development of PDA and its progression to metastatic disease. There was a statistically significant loss of STAG2 protein expression in human tumor tissue (Wilcoxon-Rank test) with complete absence of STAG2 staining observed in 15 (4.3%) patients. In univariate Kaplan Meier analysis nearly complete STAG2 positive staining (> 95% of nuclei positive) was associated with a median survival benefit of 6.41 months (p = 0.031). The survival benefit of adjuvant chemotherapy was only seen in patients with a STAG2 staining of less than 95% (median survival benefit 7.65 months; p = 0.028). Multivariate Cox Regression analysis showed that STAG2 is an independent prognostic factor for survival in pancreatic cancer patients. Finally we show that RNAi mediated knockdown of STAG2 selectively sensitizes human PDA cell lines to platinum-based therapy. We used DNA content flow sorting to identify and purify tumor nuclei of PDA samples from 50 patients. The genome of each sorted sample was profiled by oligonucleotide comparative genomic hybridization (aCGH) and targeted resequencing of STAG2. Transposon insertions within STAG2 in a KRASG12D driven genetically engineered mouse (GEM) model of PDA were screened by RT-PCR. We then used a tissue microarray (TMA) to survey STAG2 protein expression levels in 344 human PDA tumor samples and adjacent tissues. Univariate Kaplan Meier analysis and multivariate Cox Regression analysis was used to assess the association of STAG2 expression relative to overall survival and responses to adjuvant therapy. Finally RNAi based assays with PDA cell lines were used to assess the potential therapeutic consequence of STAG2 expression in responses to 18 therapeutic agents.
2014-01-24 | E-GEOD-54328 | biostudies-arrayexpress
Project description:Background: Long noncoding RNAs (lncRNAs) are pervasively transcribed and play a key role in tumorigenesis. The aim of the present study was to determine the lncRNA expression profile in astrocytoma patients and to assess the potential clinical value of the findings. Methods: The global lncRNA expression profile in astrocytoma was measured by lncRNA microarray. Next, the differentially expressed lncRNAs were validated using a Taqman probe-based quantitative real time-PCR (qRT-PCR) assay in 130 astrocytoma and 60 normal adjacent tissue (NAT) samples, which were randomly divided into a training set and a validation set. Finally, the correlation of the lncRNA levels with survival of the astrocytoma patients was estimated by performing a Kaplan-Meier survival analysis and a univariate/multivariate Cox proportional hazard regression analysis. Results: After a two-phase selection and validation process, 7 lncRNAs were found to have a significantly different expression profile in astrocytoma samples compared to the NAT samples. Unsupervised clustering analysis further revealed the potential of the 7-lncRNA profile to differentiate between tumors and NAT samples. Using Kaplan-Meier survival analysis, we found that the low expression of XLOC_005285 and XLOC_010967 and the high expression of HIT000260843.11 were significantly associated with poor patient survival. Moreover, Cox proportional hazard regression analysis revealed that this prognostic impact was independent of other clinicopathological factors. The lncRNA expression profiles of 3 astrocytoma tissues and 3 normal adjacent tissues were studied by microarray.
2014-06-07 | E-GEOD-58276 | biostudies-arrayexpress
Project description:Background: Long noncoding RNAs (lncRNAs) are pervasively transcribed and play a key role in tumorigenesis. The aim of the present study was to determine the lncRNA expression profile in astrocytoma patients and to assess the potential clinical value of the findings. Methods: The global lncRNA expression profile in astrocytoma was measured by lncRNA microarray. Next, the differentially expressed lncRNAs were validated using a Taqman probe-based quantitative real time-PCR (qRT-PCR) assay in 130 astrocytoma and 60 normal adjacent tissue (NAT) samples, which were randomly divided into a training set and a validation set. Finally, the correlation of the lncRNA levels with survival of the astrocytoma patients was estimated by performing a Kaplan-Meier survival analysis and a univariate/multivariate Cox proportional hazard regression analysis. Results: After a two-phase selection and validation process, 7 lncRNAs were found to have a significantly different expression profile in astrocytoma samples compared to the NAT samples. Unsupervised clustering analysis further revealed the potential of the 7-lncRNA profile to differentiate between tumors and NAT samples. Using Kaplan-Meier survival analysis, we found that the low expression of XLOC_005285 and XLOC_010967 and the high expression of HIT000260843.11 were significantly associated with poor patient survival. Moreover, Cox proportional hazard regression analysis revealed that this prognostic impact was independent of other clinicopathological factors.
2014-06-07 | GSE58276 | GEO
Project description:Chemoradiation therapy (CRT) is a treatment for muscle invasive bladder cancer (MIBC). Using a novel transcriptomic profiling panel, we validated prognostic immune biomarkers for response to CRT on 70 pre-treatment tumor samples from NRG/RTOG 0524 and 0712, two prospective trials of MIBC. Disease-free survival (DFS) and overall survival (OS) was estimated by Kaplan-Meier method and stratified by genes correlated with immune cell proportions and activation. Cox proportional hazards models were used to assess group differences. Sample clustering based on gene expression profiles driven by immune cell proportions demonstrated cluster 2 with a high percentage of immune cell content with significantly longer DFS (Hazard Ratio (HR): 0.53 (95% CI: 0.26 – 1.10), p=0.071) and OS (HR: 0.48 (95% CI: 0.24 – 0.97), p=0.040) than cluster 1 with a low percentage of immune cell content. Higher expression of T cell infiltration genes (CD8A and ICOS ) showed longer DFS (HR: 0.40 (95% CI: 0.21 – 0.75), p=0.005) and OS (HR: 0.49 (95% CI: 0.25 – 0.94), p=0.033). Higher expression of interferon gamma signaling (IDO1) also showed longer DFS (HR: 0.44 (95% CI: 0.24 – 0.88), p=0.021) and OS (HR: 0.49 (95% CI: 0.24 – 0.99), p=0.048). These findings have treatment implications that should be validated in CRT MIBC trials particularly those that integrate immunotherapy.
2023-12-31 | GSE245748 | GEO
Project description:Background: New molecular biomarkers for prostate cancer (PC) prognosis are urgently needed. Ratio-based models are attractive, as they require no additional normalization. Here, we train and independently validate a novel 4-miRNA prognostic ratio model for PC. Patients and methods: By genome-wide miRNA expression profiling of PC tissue samples from 123 men who underwent radical prostatectomy (RP) (PCA123, training cohort), we identified six top candidate prognostic miRNAs and systematically tested their ability to predict post-operative biochemical recurrence (BCR). The best miRNA-based prognostic ratio model (MiCaP) was validated in two independent cohorts (PCA352 and PCA476) including >800 RP patients in total. Clinical endpoints were BCR and prostate cancer-specific survival (CSS). The prognostic potential of MiCaP was assessed by univariate and multivariate Cox-regression analyses and Kaplan-Meier analyses. Results: We identified a 4-miRNA ratio model, MiCaP (miR-23a-3p×miR-10b-5p)/(miR-133a×miR-374b-5p), that predicted time to BCR independently of routine clinicopathological variables in the training cohort (PCA123) and was successfully validated in two independent RP cohorts. In addition, MiCaP was a significant predictor of CSS in univariate analysis (HR 3·35 [95% CI 1·34 – 8·35], P=0·0096) and in multivariate analysis (HR 2·43 [95% CI 1·45 – 4·07], P=0·0210). Limitations include low mortality rates (CSS: 5.4%). Conclusions: We identified a novel 4-miRNA ratio model (MiCaP) with significant independent prognostic value in three RP cohorts, indicating promising potential to improve PC risk stratification.
2018-08-14 | GSE115402 | GEO
Project description:The oxidoreductase protein disulfide isomerase A1 (PDIA1) functions as a cofactor for many transcription factors including the estrogen receptor alpha (ERα), the NF-κΒ, the nuclear factor erythroid 2-like 2 (NRF2) and regulates the protein stability of the tumor suppressor p53. Taking this into account we hypothesized that PDIA1, by differentially modulating the gene expression of diverse subsets of genes in the ERα positive versus the ERα negative breast cancer cells, modifies dissimilar pathways in the two types of breast cancer. This hypothesis was investigated using RNA-seq data from PDIA1-silenced MCF-7 (ERα+) and MDA-MB-231 (ERα-) breast cancer cells treated with either interferon gamma (IFN-γ) or etoposide (ETO) and the obtained data were further analyzed using a variety of bioinformatic tools alongside clinical relevance assessment via Kaplan-Meier patient survival curves. The results highlighted the dual role of PDIA1 in suppressing carcinogenesis in the ERα+ breast cancer patients by negatively regulating the response to reactive oxygen species and promoting carcinogenesis by inducing cell cycle progression. In the ERα- breast cancer patients PDIA1 prevents tumor development by regulating the NF-kappa B and p53 by modulating cell migration and inducing breast cancer progression through control of cytokine signaling and the immune response. The findings reported in this study shed light on the differential pathways regulating carcinogenesis in the ERα+ and ERα- breast cancer patients and could help identify therapeutic targets selectively effective in the ERα+ versus the ERα- patients.
2021-11-18 | GSE188914 | GEO