scholarly journals 5mC regulator-mediated molecular subtypes depict the hallmarks of the tumor microenvironment and guide precision medicine in bladder cancer

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jiao Hu ◽  
Belaydi Othmane ◽  
Anze Yu ◽  
Huihuang Li ◽  
Zhiyong Cai ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Precision Medicine ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Antiangiogenic Therapy ◽  
Principal Component ◽  
High Sensitivity ◽  
Ppar Γ ◽  
Low Sensitivity

Abstract Background Depicting the heterogeneity and functional characteristics of the tumor microenvironment (TME) is necessary to achieve precision medicine for bladder cancer (BLCA). Although classical molecular subtypes effectively reflect TME heterogeneity and characteristics, their clinical application is limited by several issues. Methods In this study, we integrated the Xiangya cohort and multiple external BLCA cohorts to develop a novel 5-methylcytosine (5mC) regulator-mediated molecular subtype system and a corresponding quantitative indicator, the 5mC score. Unsupervised clustering was performed to identify novel 5mC regulator-mediated molecular subtypes. The principal component analysis was applied to calculate the 5mC score. Then, we correlated the 5mC clusters (5mC score) with classical molecular subtypes, immunophenotypes, clinical outcomes, and therapeutic opportunities in BLCA. Finally, we performed pancancer analyses on the 5mC score. Results Two 5mC clusters, including 5mC cluster 1 and cluster 2, were identified. These novel 5mC clusters (5mC score) could accurately predict classical molecular subtypes, immunophenotypes, prognosis, and therapeutic opportunities of BLCA. 5mC cluster 1 (high 5mC score) indicated a luminal subtype and noninflamed phenotype, characterized by lower anticancer immunity but better prognosis. Moreover, 5mC cluster 1 (high 5mC score) predicted low sensitivity to cancer immunotherapy, neoadjuvant chemotherapy, and radiotherapy, but high sensitivity to antiangiogenic therapy and targeted therapies, such as blocking the β-catenin, FGFR3, and PPAR-γ pathways. Conclusions The novel 5mC regulator-based subtype system reflects many aspects of BLCA biology and provides new insights into precision medicine in BLCA. Furthermore, the 5mC score may be a generalizable predictor of immunotherapy response and prognosis in pancancers.

scholarly journals Therapeutic Responses to Chemotherapy or Immunotherapy by Molecular Subtype in Bladder Cancer Patients: A Meta-Analysis and Systematic Review

2021 ◽  
Author(s):  
Shunde Wang ◽  
Xiaoyu Yuan ◽  
Chengguo Ge ◽  
Junyong Zhang ◽  
Zhongjie Shen ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Therapeutic Response ◽  
Response Rate ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Meta Analysis ◽  
Response Rates ◽  
Cancer Treatments ◽  
Response To Chemotherapy ◽  
Neo Adjuvant Chemotherapy

Abstract Background Bladder cancer (BC) is a heterogeneous disease characterized by high recurrence and a poor prognosis. Molecular subtypes of BC portend personalized and precision medicine. However, whether there is a difference in therapeutic response to chemotherapy or immunotherapy between different molecular subtypes of BC has not been systematically evaluated.Methods A comprehensive literature search was performed up to October 2020. Consensus clusters 1 (CC1), CC2 and CC3 molecular subtypes were defined according to the heterogeneity and similarity of BC molecular subtypes from published studies to perform meta-analysis. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the therapeutic response, and a fixed- or random-effects model was used according to the existence of heterogeneity.Results Eight studies involving 1463 patients were included in this research. For immunotherapy, CC3 showed the highest respond rate (CC3 vs CC1: OR 0.52, CI [0.34–0.78], P = 0.002. CC3 vs CC2: OR 0.42, CI [0.28–0.62], P < 0.0001), which was mainly reflected in the highest response rate to atezolizumab (CC3 vs CC1: OR 0.47, CI [0.29–0.75], P = 0.002. CC3 vs CC2: OR 0.38, CI [0.24–0.59], P < 0.0001), and the response rates to nivolumab showed no advantage over CC1 and CC2. No difference in response to the two immunotherapies between CC1 and CC2. For chemotherapy, CC3 had the lowest response rate to the overall chemotherapy (CC3 vs CC1: OR 2.28, CI [1.39–3.74], P = 0.001. CC3 vs CC2: OR = 2.25, 95% CI 1.34–3.76, P = 0.002). Compared with CC2, CC3 responded poorly to both neo-adjuvant chemotherapy (NAC) (OR 1.93, CI [1.09–3.41], P = 0.02) and chemoradiation therapy (CRT) (OR 4.53, CI [1.26–16.27], P = 0.02). Compared with CC1, CC3 only showed a poorer response to CRT (OR 6.07, CI [1.87–19.71], P = 0.003), and no difference in NAC. No difference between CC1 and CC2 subtypes in the response rates to NAC and CRT.Conclusions Our study suggested that molecular classifications are important predictors of cancer treatment outcomes of BC patients and could identify subgroup patients who are most likely to benefit from specific cancer treatments.

scholarly journals Defining muscle-invasive bladder cancer immunotypes by introducing tumor mutation burden, CD8+ T cells, and molecular subtypes

Hereditas ◽  
2021 ◽  
Vol 158 (1) ◽  
Author(s):  
Zihao Chen ◽  
Guojun Liu ◽  
Guoqing Liu ◽  
Mikhail A. Bolkov ◽  
Khyber Shinwari ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Signaling Pathway ◽  
Cd8 T Cells ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Muscle Invasive Bladder Cancer ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Muscle Invasive

AbstractImmunotherapy, especially anti-PD-1, is becoming a pillar of modern muscle-invasive bladder cancer (MIBC) treatment. However, the objective response rates (ORR) are relatively low due to the lack of precise biomarkers to select patients. Herein, the molecular subtype, tumor mutation burden (TMB), and CD8+ T cells were calculated by the gene expression and mutation profiles of MIBC patients. MIBC immunotypes were constructed using clustering analysis based on tumor mutation burden, CD8+ T cells, and molecular subtypes. Mutated genes, enriched functional KEGG pathways and GO terms, and co-expressed network-specific hub genes have been identified. We demonstrated that ORR of immunotype A patients identified by molecular subtype, CD8+ T cells, and TMB is about 36% predictable. PIK3CA, RB1, FGFR3, KMT2C, MACF1, RYR2, and EP300 are differentially mutated among three immunotypes. Pathways such as ECM-receptor interaction, PI3K-Akt signaling pathway, and TGF-beta signaling pathway are top-ranked in enrichment analysis. Low expression of ACTA2 was associated with the MIBC survival benefit. The current study constructs a model that could identify suitable MIBC patients for immunotherapy, and it is an important step forward to the personalized treatment of bladder cancers.

scholarly journals Siglec15 shapes a non-inflamed tumor microenvironment and predicts the molecular subtype in bladder cancer

Theranostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 3089-3108
Author(s):  
Jiao Hu ◽  
Anze Yu ◽  
Belaydi Othmane ◽  
Dongxu Qiu ◽  
Huihuang Li ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Molecular Subtype

Muscle invasive bladder cancer (MIBC) demonstrates neoadjuvant cisplatin-based chemotherapy (NAC) related changes in molecular subtype and immune infiltration.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 443-443
Author(s):  
Samuel Aaron Funt ◽  
Alexander Solovyov ◽  
Bishoy Morris Faltas ◽  
Gopa Iyer ◽  
Mariel Elena Boyd ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Bladder Tumor ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Expression Patterns ◽  
The Cancer Genome Atlas ◽  
Rna Expression ◽  
Cancer Therapies ◽  
Primary Bladder ◽  
Muscle Invasive

443 Background: Defining the role of MIBC molecular subtypes and immune expression in determining clinical outcomes is an area of active investigation. However, changes in these transcriptomic profiles pre- and post-NAC have not been well characterized. Methods: This retrospective study reviewed 53 pts with MIBC treated with NAC, of whom 12 pts without complete pathological response had both pre- and post-NAC samples of sufficient quality. Post-NAC staging was > = pT2 in 11 pts and pT1 in 1 pt. We performed RNA expression analysis of matched pre-NAC transurethral resection of bladder tumor specimens and post-treatment radical cystectomy primary bladder tumor specimens. We used a customized NanoString panel incorporating previously reported immune signatures (Ayers, JCI 2017; O’Donnell, ASCO 2017) and additional genes to assign basal ( CD14, CD44, PDGFC, KRT14, KRT5) and luminal ( GATA3, PPARG, SHH, CD24, FOXA1, WNT7B, ERBB2) molecular subtypes. Results: We first classified the bladder cancer cohort of The Cancer Genome Atlas into basal and luminal subtypes using the BASE47 signature (Damrauer, PNAS 2014) and the NanoString panel and there was good agreement (Rand Index = 0.72). We then assigned subtypes using the NanoString panel on matched pre- and post-NAC samples and found marked subtype shift (Table). We identified two robust clusters of samples according to immune expression with a 3-fold change of immune expression between them (FDR = 0.0008). We found that 4 pts switched from the low to the high cluster, while 2 switched from the high to the low cluster after NAC (Table). Conclusions: MIBC molecular subtype membership is dynamic and is influenced by NAC. NAC can induce both enhanced and suppressed immune activity. These findings have implications on future studies exploring the predictive value of RNA expression patterns for bladder cancer therapies as well as post-NAC immunotherapy. [Table: see text]

scholarly journals A Novel Assessment Model Based on Molecular Subtypes of Hypoxia-Related LncRNAs for Prognosis of Bladder Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Xianwu Chen ◽  
Yan Zhang ◽  
Feifan Wang ◽  
Xuejian Zhou ◽  
Qinghe Fu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Risk Model ◽  
Cox Regression ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Tumor Therapy ◽  
Assessment Model ◽  
Immune Checkpoints ◽  
Cox Regression Analysis ◽  
Model Based

Hypoxia is a common feature in various tumors that regulates aggressiveness. Previous studies have demonstrated that some dysregulated long non-coding RNAs (lncRNAs) are correlated with tumor progression, including bladder cancer (BCa). However, the prognostic effect of hypoxia-related lncRNAs (HRLs) and their clinical relevance, as well as their regulatory effect on the tumor immune microenvironment, are largely unknown in BCa. A co-expression analysis between hypoxia genes and lncRNA expression, which was downloaded from the TCGA database, was performed to identify HRLs. Univariate Cox regression analysis was performed to select the most desirable lncRNAs for molecular subtype, and further LASSO analysis was performed to develop a prognostic model. This molecular subtype based on four HRLs (AC104653, AL136084, AL139393, and LINC00892) showed good performance in the tumor microenvironment and tumor mutation burden. The prognostic risk model suggested better performance in predicting BCa patients’ prognosis and obtained a close correlation with clinicopathologic features. Furthermore, four of five first-line clinical chemotherapies showed different sensitivities to this model, and nine immune checkpoints showed different expression in the molecular subtypes or the risk model. In conclusion, this study indicates that this molecular subtype and risk model based on HRLs may be useful in improving the prognostic prediction of BCa patients with different clinical situations and may help to find a useful target for tumor therapy.

scholarly journals Defining muscle-invasive bladder cancer immunotypes by introducing tumor mutation burden, CD8+ T cells, and molecular subtypes

2020 ◽  
Author(s):  
Zihao Chen ◽  
Guojun Liu ◽  
Guoqing Liu ◽  
Mikhail A. Bolkov ◽  
Khyber Shinwari ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Signaling Pathway ◽  
Cd8 T Cells ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Muscle Invasive Bladder Cancer ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Muscle Invasive

Abstract Immunotherapy, especially anti-PD-1, is becoming a pillar of modern muscle-invasive bladder cancer (MIBC) treatment. However, the objective response rates (ORR) are relatively low due to the lack of precise biomarkers to select patients. Herein, the molecular subtype, tumor mutation burden (TMB), and CD8+ T cells were calculated by the gene expression and mutation profiles of MIBC patients. MIBC immunotypes were constructed using clustering analysis based on tumor mutation burden, CD8+ T cells, and molecular subtypes. Mutated genes, enriched functional KEGG pathways and GO terms, and co-expressed network-specific hub genes have been identified. We demonstrated that ORR of immunotype A patients identified by molecular subtype, CD8+ T cells, and TMB is about 36% predictable. PIK3CA , RB1 , FGFR3 , KMT2C , MACF1 , RYR2 , and EP300 are differentially mutated among three immunotypes. Pathways such as ECM-receptor interaction, PI3K-Akt signaling pathway, and TGF-beta signaling pathway are top-ranked in enrichment analysis. Low expression of ACTA2 was associated with the MIBC survival benefit. The current study constructs a model that could identify suitable MIBC patients for immunotherapy, and it is an important step forward to the personalized treatment of bladder cancers.Immunotherapy, especially anti-PD-1, is becoming a pillar of modern muscle-invasive bladder cancer (MIBC) treatment. However, the objective response rates (ORR) are relatively low due to the lack of precise biomarkers to select patients. Herein, the molecular subtype, tumor mutation burden (TMB), and CD8+ T cells were calculated by the gene expression and mutation profiles of MIBC patients. MIBC immunotypes were constructed using clustering analysis based on tumor mutation burden, CD8+ T cells, and molecular subtypes. Mutated genes, enriched functional KEGG pathways and GO terms, and co-expressed network-specific hub genes have been identified. We demonstrated that ORR of immunotype A patients identified by molecular subtype, CD8+ T cells, and TMB is about 36% predictable. PIK3CA , RB1 , FGFR3 , KMT2C , MACF1 , RYR2 , and EP300 are differentially mutated among three immunotypes. Pathways such as ECM-receptor interaction, PI3K-Akt signaling pathway, and TGF-beta signaling pathway are top-ranked in enrichment analysis. Low expression of ACTA2 was associated with the MIBC survival benefit. The current study constructs a model that could identify suitable MIBC patients for immunotherapy, and it is an important step forward to the personalized treatment of bladder cancers.

scholarly journals Pyroptosis Patterns Characterized by Distinct Tumor Microenvironment Infiltration Landscapes in Gastric Cancer

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1535
Author(s):  
Renshen Xiang ◽  
Yuhang Ge ◽  
Wei Song ◽  
Jun Ren ◽  
Can Kong ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Microenvironment ◽  
Molecular Subtypes ◽  
Principal Component ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Consensus Clustering ◽  
Analysis Algorithm ◽  
Signature Genes

Background: The potential role of pyroptosis in tumor microenvironment (TME) reprogramming and immunotherapy has received increasing attention. As most studies have concentrated on a single TME cell type or a single pyroptosis regulator (PR), the overall TME cell-infiltrating characteristics mediated by the integrated roles of multiple PRs have not been comprehensively recognized. Methods: This study curated 33 PRs and conducted consensus clustering to identify distinct pyroptosis patterns in gastric cancer (GC) patients. A single-sample gene set enrichment analysis algorithm was used to quantify the infiltration density of TME immune cells and the enrichment scores of well-defined biological signatures. The pyroptosis patterns of individuals were quantified using a principal component analysis algorithm called the pyroptosis score (PS). Results: Three distinct pyroptosis patterns with significant survival differences were identified from 1422 GC samples; these patterns were closely associated with three TME cell-infiltrating landscapes—namely, the immune-inflamed, immune-excluded, and immune-desert phenotypes. The PS model generated on the basis of the pyroptosis pattern-related signature genes could accurately predict the TME status, existing molecular subtypes, genetic variation, therapeutic response, and clinical outcome; among which, a relatively high PS was highly consistent with immune activation, molecular subtypes with survival advantages, high tumor mutation burden, high microsatellite instability, and other favorable characteristics. In particular, from the Cancer Genome Atlas database, the PS model exhibited significant prognostic relevance in a pan-cancer analysis, and patients with a relatively high PS exhibited durable therapeutic advantages and better prognostic benefits in anti-PD1/L1 therapy. Conclusions: This study demonstrates that pyroptosis is prominently correlated with TME diversity and complexity, and quantification of the pyroptosis patterns of individuals will enhance our cognition of TME infiltration landscapes and help in formulating more effective immunotherapeutic strategies.

scholarly journals Unraveling Triple-Negative Breast Cancer Tumor Microenvironment Heterogeneity: Towards an Optimized Treatment Approach

2019 ◽  
Vol 112 (7) ◽  
pp. 708-719 ◽  
Author(s):  
Yacine Bareche ◽  
Laurence Buisseret ◽  
Tina Gruosso ◽  
Edwina Girard ◽  
David Venet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Tumor Microenvironment ◽  
Spatial Pattern ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Statistical Tests ◽  
Copy Number Loss

Abstract Background Recent efforts of gene expression profiling analyses recognized at least four different triple-negative breast cancer (TNBC) molecular subtypes. However, little is known regarding their tumor microenvironment (TME) heterogeneity. Methods Here, we investigated TME heterogeneity within each TNBC molecular subtype, including immune infiltrate localization and composition together with expression of targetable immune pathways, using publicly available transcriptomic and genomic datasets from a large TNBC series totaling 1512 samples. Associations between molecular subtypes and specific features were assessed using logistic regression models. All statistical tests were two-sided. Results We demonstrated that each TNBC molecular subtype exhibits distinct TME profiles associated with specific immune, vascularization, stroma, and metabolism biological processes together with specific immune composition and localization. The immunomodulatory subtype was associated with the highest expression of adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check point inhibitors. In contrast, most mesenchymal stem-like and luminal androgen receptor tumors showed an immunosuppressive phenotype as witnessed by high expression levels of stromal signatures. Basal-like, luminal androgen receptor, and mesenchymal subtypes exhibited an immune cold phenotype associated with stromal and metabolism TME signatures and enriched in margin-restricted spatial pattern. Tumors with high chromosomal instability and copy number loss in the chromosome 5q and 15q regions, including genomic loss of major histocompatibility complex related genes, showed reduced cytotoxic activity as a plausible immune escape mechanism. Conclusions Our results demonstrate that each TNBC subtype is associated with specific TME profiles, setting the ground for a rationale tailoring of immunotherapy in TNBC patients.

scholarly journals Defining muscle-invasive bladder cancer immunotypes by introducing tumor mutation burden, CD8+ T cells, and molecular subtypes

2020 ◽  
Author(s):  
Zihao Chen ◽  
Guojun Liu ◽  
Guoqing Liu ◽  
Mikhail A. Bolkov ◽  
Irina A. Tuzankina ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Signaling Pathway ◽  
Cd8 T Cells ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Muscle Invasive Bladder Cancer ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Muscle Invasive

Abstract Immunotherapy, especially anti-PD-1, is becoming a pillar of modern muscle-invasive bladder cancer (MIBC) treatment. However, the objective response rates (ORR) are relatively low due to the lack of precise biomarkers to select patients. Herein, the molecular subtype, tumor mutation burden (TMB), and CD8 + T cells were calculated by the gene expression and mutation profiles of MIBC patients. MIBC immunotypes were constructed using clustering analysis based on tumor mutation burden, CD8 + T cells, and molecular subtypes. Mutated genes, KEGG pathways, GO terms, and co-expressed network-specific hub genes have been identified. We demonstrated that ORR of immunotype A patients identified by molecular subtype, CD8 + T cells, and TMB is about 36% predictable. PIK3CA, RB1, FGFR3, KMT2C, MACF1, RYR2, and EP300 are differentially mutated among three immunotypes. Pathways such as ECM-receptor interaction, PI3K-Akt signaling pathway, and TGF-beta signaling pathway are top-ranked in enrichment analysis. Low expression of ACTA2 was associated with the MIBC survival benefit. This study identified which MIBC patients are suitable for immunotherapy, and it is an important step forward to the personalized treatment of bladder cancers.

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