scholarly journals Metabolic classification of bladder cancer based on multi-omics integrated analysis to predict patient prognosis and treatment response

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Chaozhi Tang ◽  
Meng Yu ◽  
Jiakang Ma ◽  
Yuyan Zhu
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Metabolic Activity ◽  
Survival Data ◽  
Cancer Metabolism ◽  
Prognostic Significance ◽  
Integrated Analysis ◽  
Metabolic Characteristics ◽  
Metabolic Genes

Abstract Background Currently, no molecular classification is established for bladder cancer based on metabolic characteristics. Therefore, we conducted a comprehensive analysis of bladder cancer metabolism-related genes using multiple publicly available datasets and aimed to identify subtypes according to distinctive metabolic characteristics. Methods RNA-sequencing data of The Cancer Genome Atlas were subjected to non-negative matrix fractionation to classify bladder cancer according to metabolism-related gene expression; Gene Expression Omnibus and ArrayExpress datasets were used as validation cohorts. The sensitivity of metabolic types to predicted immunotherapy and chemotherapy was assessed. Kaplan–Meier curves were plotted to assess patient survival. Differentially expressed genes between subtypes were identified using edgeR. The differences among identified subtypes were compared using the Kruskal–Wallis non-parametric test. To better clarify the subtypes of bladder cancer, their relationship with clinical characteristics was examined using the Fisher’s test. We also constructed a risk prediction model using the random survival forest method to analyze right-censored survival data based on key metabolic genes. To identify genes of prognostic significance, univariate Cox regression, lasso analysis, and multivariate regression were performed sequentially. Results Three bladder cancer subtypes were identified according to the expression of metabolism-related genes. The M1 subtype was characterized by high metabolic activity, low immunogenicity, and better prognosis. M2 exhibited moderate metabolic activity, high immunogenicity, and the worst prognosis. M3 was associated with low metabolic activity, low immunogenicity, and poor prognosis. M1 showed the best predicted response to immunotherapy, whereas patients with M1 were predicted to be the least sensitive to cisplatin. By contrast, M2 showed the worst predicted response to immunotherapy but was predicted to be more sensitive to cisplatin, doxorubicin, and other first-line anticancer drugs. M3 was the most sensitive to gemcitabine. The risk model based on metabolic genes effectively predicted the prognosis of bladder cancer patients. Conclusions Metabolic classification of bladder cancer has potential clinical value and therapeutic feasibility by inhibiting the associated pathways. This classification can provide valuable insights for developing precise bladder cancer treatment.

scholarly journals A novel molecular classification of diffuse large B cell lymphoma based on Metabolism-related genes

2020 ◽  
Author(s):  
ying duan ◽  
Yanzhen Luo ◽  
hong cen
Keyword(s):  
B Cell ◽  
Metabolic Activity ◽  
Immune Escape ◽  
Cell Lymphoma ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Molecular Heterogeneity ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Purpose About 30–40% of patients with diffuse large B-cell lymphoma (DLBCL) relapse or fail to respond to first-line treatment. The molecular heterogeneity is considered to be the main factor affecting the therapeutic response of DLBCL. The existing classification methods can not fully explain these heterogeneity, so we try to explain DLBCL heterogeneity by defining DLBCL subtypes from the perspective of metabolism. Methods In this study, we integrated five DLBCL data sets (GSE10846, GSE11318, GSE53786, GSE87371 and GSE23501) (n = 742) from geo database, screened 106 metabolic related genes (MAD > 0.5, Cox P < 0.001), and identified dlbcl2 subclasses (nmftype1, nmftype2) by non-negative matrix factorization clustering (NMF). Results nmftype1 showed low metabolic activity ,while nmftype2 showed high metabolic activity. Compared with the two subtypes of immune infiltration, it was found that nmftype1 was mainly infiltrated by B cells, and nmftype2 was mainly infiltrated by T cells and macrophages, and the high expression of nmftype2 was more in immune checkpoint. The difference of metabolic subtype OS was statistically significant, and the overall survival (OS) of nfmtype1 was worse than that of nmftype2. The combination of metabolic subtypes and ABCGCB subtypes can predict the prognosis of DLBCL patients better than the existing ABCGCB subtypes. Finally, 34 gene classifiers were identified. The consistency results were verified by GSE31312 (n = 470), and a new classification of DLBCL based on metabolic gene expression profile was established. Conclusions We have obtained a new DLBCL typing method, which has prognostic significance. It has a certain correlation with immune escape and can guide individualization application of immunotherapy and metabolic therapy.

scholarly journals Overexpression of PSAT1 Gene is a Favorable Prognostic Marker in Lower-Grade Gliomas and Predicts a Favorable Outcome in Patients with IDH1 Mutations and Chromosome 1p19q Codeletion

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 13 ◽  
Author(s):  
Shang-Pen Huang ◽  
Yung-Chieh Chan ◽  
Shang-Yu Huang ◽  
Yuan-Feng Lin
Keyword(s):  
Gene Expression ◽  
Prognostic Marker ◽  
Cancer Metabolism ◽  
Prognostic Significance ◽  
Favorable Outcome ◽  
Lower Grade ◽  
1P19q Codeletion ◽  
Potential Biomarker ◽  
Idh1 Mutations ◽  
Genome Atlas

Patients with lower-grade gliomas (LGGs) have highly diverse clinical outcomes. Although histological features and molecular markers have been used to predict prognosis, the identification of new biomarkers for the accurate prediction of patient outcomes is still needed. The serine synthesis pathway (SSP) is important in cancer metabolism. There are three key regulators, including phosphoglycerate dehydrogenase (PHGDH), phosphoserine phosphatase (PSPH), and phosphoserine aminotransferase 1 (PSAT1), in SSP. However, their clinical importance in LGGs is still unknown. In this study, we used the bioinformatics tool in the Gene Expression Profiling Interactive Analysis (GEPIA) website to examine the prognostic significance of PHGDH, PSPH, and PSAT1 genes in LGGs. PSAT1 gene expression was then identified as a potential biomarker candidate for LGGs. Datasets from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) were further used to explore the prognostic role of PSAT1 gene. Our results demonstrated that PSAT1 overexpression is a favorable prognostic marker of LGGs and significantly correlated with patient age ≤40, and a lower WHO histological grade, as well as mutations in IDH1, TP53 and ATRX, but not with chromosome 1p19q codeletions. More importantly, LGG patients with isocitrate dehydrogenase 1 (IDH1) mutations, chromosome 1p19q codeletions, and PSAT1 overexpression may have the best overall survival (five-year survival rate: 100%). Finally, we observed a coordinated biological reaction between IDH1 mutations and PSAT1 overexpression, and suggested overexpression of PSAT1 might enhance the function of mutant IDH1 to promote a favorable outcome in LGG patients. In conclusion, our study confirmed the importance of identifying the overexpression of PSAT1 as a favorable prognostic marker of LGGs, which may compensate for the limitation of IDH1 mutations and chromosome 1p19q codeletion in the prognostication of LGGs.

scholarly journals Gene Expression, DNA Methylation and Prognostic Significance of DNA Repair Genes in Human Bladder Cancer

2017 ◽  
Vol 42 (6) ◽  
pp. 2404-2417 ◽  
Author(s):  
Anita Wojtczyk-Miaskowska ◽  
Malgorzata Presler ◽  
Jerzy Michajlowski ◽  
Marcin Matuszewski ◽  
Beata Schlichtholz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Bladder Cancer ◽  
Dna Repair ◽  
Mrna Expression ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Prognostic Significance ◽  
Muscle Invasive ◽  
Repair Genes

Background/Aims: This study investigated the gene expression and DNA methylation of selected DNA repair genes (MBD4, TDG, MLH1, MLH3) and DNMT1 in human bladder cancer in the context of pathophysiological and prognostic significance. Methods: To determine the relationship between the gene expression pattern, global methylation and promoter methylation status, we performed real-time PCR to quantify the mRNA of selected genes in 50 samples of bladder cancer and adjacent non-cancerous tissue. The methylation status was analyzed by methylation-specific polymerase chain reaction (MSP) or digestion of genomic DNA with a methylation-sensitive restriction enzyme and PCR with gene-specific primers (MSRE-PCR). The global DNA methylation level was measured using the antibody-based 5-mC detection method. Results: The relative levels of mRNA for MBD4, MLH3, and MLH1 were decreased in 28% (14/50), 34% (17/50) and 36% (18/50) of tumor samples, respectively. The MBD4 mRNA expression was decreased in 46% of non-muscle invasive tumors (Ta/T1) compared with 11% found in muscle invasive tumors (T2-T4) (P<0.003). Analysis of mRNA expression for TDG did not show any significant differences between Ta/T1 and T2-T4 tumors. The frequency of increased DNMT1 mRNA expression was higher in T2-T4 (52%) comparing to Ta/T1 (16%). The overall methylation rates in tumor tissue were 18% for MBD4, 25% for MLH1 and there was no evidence of MLH3 promoter methylation. High grade tumors had significantly lower levels of global DNA methylation (P=0.04). There was a significant association between shorter survival and increased expression of DNMT1 mRNA (P=0.002), decreased expression of MLH1 mRNA (P=0.032) and the presence of MLH1 promoter methylation (P=0.006). Conclusion: This study highlights the importance of DNA repair pathways and provides the first evidence of the role of MBD4 and MLH3 in bladder cancer. In addition, our findings suggest that DNMT1 mRNA and MLH1 mRNA expression, as well as the status of MLH1 promoter methylation, are attractive prognostic markers in this pathology.

Expression of EGFR, HER-2 and p53 predictive of prognosis in muscle-invasive bladder cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15637-15637 ◽  
Author(s):  
W. Sakr ◽  
S. Marur ◽  
M. Che ◽  
L. Heilbrun ◽  
D. Smith ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Survival Data ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Growth Factor Receptor ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Female Ratio ◽  
Her 2 ◽  
Muscle Invasive

15637 Background: The significance of over expression of Erb-1 (epidermal growth factor receptor/ EGFR) and Erb-2 (Her-2) has been reported in various tumors. The aim of this study was to investigate the correlation of the expression of EGFR, Her-2 and p53 with relapse free survival (RFS) and over all survival (OS) in patients with muscle invasive bladder cancer Methods: All patients with muscle invasive bladder cancer diagnosed at our institution between1993and 2004 were considered for the study. Immunohistochemical staining for EGFR, Her2 and p53 performed on formalin-fixed paraffin-embedded archival tissue was evaluated as positive or negative without knowledge of clinical outcome. Survival data determined by reviewing patients medical records were correlated with the staining results. Results: Of the 46 patients who qualified for the study, 40 had slides interpretable for Her 2 and p 53 staining and 38 had slides interpretable for EGFR staining. 35 of 38 were EGFR +ve, 22/40 were Her-2 +ve and 12/40 were p53+ve. The median age of the 46 patients was 67.5 years with a male/female ratio of 60% and 40%. 83% had clinical Stage 2; of those 42%, 23%, and 35% had pathological stages T2, T3 and T4 respectively. Six of 46 (13%), received adjuvant therapy. Tumor histology was pure transitional carcinoma in 56%, or with other components (squamous or adenocarcinoma) in 44%. Median follow-up was 48.8 months for RFS and 44.9 months for OS. Patients with positive EGFR had a median RFS of 34.8 months and median OS of 59.8 months. In patients with negative EGFR, median RFS and OS were not yet reached. Her 2 positive patients had median RFS of 19.2 months compared to 63.8 months in Her-2 negative patients. Her-2 negative patients had median OS of 59.7 months while median was not reached in Her 2 positive patients. Conclusions: While the differences are not statistically significant, the trends observed warrant prospective investigation of the prognostic significance of these markers in a larger population of muscle invasive bladder cancer patients. No significant financial relationships to disclose.

Microarray gene expression profiling and analysis of bladder cancer supports the sub-classification of T1 tumours into T1a and T1b stages

2013 ◽  
Vol 113 (2) ◽  
pp. 333-342 ◽  
Author(s):  
Françoise Descotes ◽  
Philippe Dessen ◽  
Pierre Paul Bringuier ◽  
Myriam Decaussin ◽  
Pierre Marie Martin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Microarray Gene Expression ◽  
Microarray Gene

scholarly journals Loss of the Pioneer Factor FOXA1 Results in Genome-wide Epigenetic Reprogramming and activation of Interferon-Response Genes including CD274/PD-L1

2020 ◽  
Author(s):  
Wenhuo Hu ◽  
Hironobu Yamashita ◽  
Jenna Craig ◽  
Vonn Walter ◽  
Joshua I. Warrick ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Transcription Factor ◽  
Epigenetic Modification ◽  
Regulatory Elements ◽  
Epigenetic Reprogramming ◽  
Gene Set Enrichment Analysis ◽  
Interferon Response ◽  
Integrated Analysis ◽  
The Impact

AbstractForkhead Box A1 (FOXA1) is a pioneer transcription factor critical in epigenetic regulation of chromatin and cell fate determination. Reduced FOXA1 expression is an independent predictor of poor overall survival in bladder cancer patients. However, the impact of FOXA1 loss on chromatin epigenetics in bladder cancer is unknown. Therefore, we determined the impact of FOXA1 knock out (KO) on epigenetic modification of chromatin and associated gene expression. We identified 8,230 differentially expressed genes following FOXA1 KO. Surprisingly, Gene Set Enrichment Analysis (GSEA) identified IFNɑ/ɣ gene expression signatures as enriched following FOXA1 KO. FOXA1 KO induced both increased and decreased numbers of histone 3 lysine 27 acetylation (H3K27ac) sites throughout the genome. As expected, the majority of differences in H3K27ac across genomic areas in FOXA1 KO cells is mapped to intergenic and intronic regions where enhancers reside. In addition, a subset of differential H3K27ac levels were also mapped to proximal promoters and within gene bodies. Integrated analysis of RNA/ChIP-seq data shows changes in gene expression that are mirrored by differences in H3K27ac. Motif analysis of DNA sequence enriched for H3K27ac identified significant increases in transcription factor binding motifs including the interferon sensitive response element (ISRE) and interferon response factors such as IRF1. Moreover, we identified increased H3K27ac of regulatory elements as being associated with several upregulated interferon sensitive genes (ISGs) in FOXA1 KO cells, including CD274/PD-L1. Western blotting and Q-RT-PCR confirmed upregulation of CD274/PD-L1 following FOXA1 KO. Analysis of TCGA data confirmed an inverse relationship between FOXA1 and CD274 in bladder cancer, as well as in other cancers. In summary, we provide evidence of widespread epigenetic reprogramming after FOXA1 KO in bladder cancer cells. Additionally, we provide evidence that FOXA1 KO-induced epigenetic changes contribute to activation of a global interferon-dominant expression signature, including the immune checkpoint target CD274/PD-L1 in a cancer cell-intrinsic manner.

scholarly journals Molecular Classification of Bladder Urothelial Carcinoma Using NanoString-Based Gene Expression Analysis

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5500
Author(s):  
Antonio Lopez-Beltran ◽  
Ana Blanca ◽  
Alessia Cimadamore ◽  
Rajan Gogna ◽  
Rodolfo Montironi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Expression Analysis ◽  
Bladder Carcinoma ◽  
Gene Expression Analysis ◽  
Molecular Classification ◽  
Cancer Specific Survival ◽  
Variant Histology

Molecular classification of bladder carcinoma is a relevant topic in modern bladder cancer oncology due to its potential to improve oncological outcomes. The available molecular classifications are generally based on transcriptomic profiles, generating highly diverse categories with limited correlation. Implementation of molecular classification in practice is typically limited due to the high complexity of the required technology, the elevated costs, and the limited availability of this technology worldwide. We have conducted a gene expression analysis using a four-gene panel related to luminal and basal subtypes in a series of 91 bladder cancer cases. NanoString-based gene expression analysis using typically luminal (GATA3+/KRT20+) and basal markers (KRT14+/KRT5+/GATA3low/-/KRT20low/-) classified urothelial bladder carcinoma samples as luminal, basal, and a third category (KRT14-/KRT5-/GATA3-/KRT20-), null/double negative (non-luminal/non-basal). These three categories were meaningful in terms of overall cancer-specific survival (p < 0.0001) or when classified as conventional urothelial carcinoma and variant histology urothelial carcinoma (p < 0.0001), NMIBC vs. MIBC (p < 0.001), or by AJCC stage category Ta (p = 0.0012) and T1 (p < 0.0001) but did not reach significance in T2-T4 (p = 0.563). PD-L1 expression (low vs. high) was also different according to molecular subtype, with high PD-L1 expression mostly seen in basal and null subtypes and carcinomas with variant histology (p = 0.002). Additionally, the luminal subtype was enriched in NMIBC with favorable cancer-specific survival (p < 0.0001). In contrast, basal and null subtypes resulted in aggressive MIBC tumors with shorter cancer-specific survival (p < 0.0001), some of which presented variant histology. In conclusion, a comprehensive evaluation of a gene classifier related to molecular taxonomy using NanoString technology is feasible. Therefore, it might represent an accessible and affordable tool in this rapidly expanding area of precision genomics.

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