Molecular Correlates of Cisplatin-based Chemotherapy Response in Muscle Invasive Bladder Cancer by Integrated Multi-omics Analysis

Taber, Ann; Christensen, Emil; Lamy, Philippe; Nordentoft, Iver; Prip, FF; Lindskrog, CV; Birkenkamp‐Demtröder, Karin; Okholm, Tlh; Knudsen, Michael; Pedersen, JS; Steiniche, Torben; Agerbæk, Mads; Jensen, J. Bjerggaard; Dyrskjøt, Lars

doi:10.1016/j.urolonc.2020.10.031

Cited by 23 publications

(45 citation statements)

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“…A recent study analyzed archived paraffin-embedded primary or metastatic tumor samples from UC patients who received palliative chemotherapy. By WES analysis, two major genomic subtypes were identified [85]. The GenS2 subtype, enriched with SigG that correlates with COSMIC SBS5, in the present study largely overlapped with the SBS5 subtype reported by Taber et al, 2020.…”

Section: Discussionsupporting

confidence: 78%

“…This suggests that mUC is in continuous adaptation by generating novel mutations. A previous study indeed reported accumulating mutations in six patients whose primary tumor and metachronous metastases were analyzed by WES [85]. In our study, the accumulation of new mutations in the sequential biopsy specimen of one of eight patients led to the identification of new therapeutic targets (Fig.…”

Section: Discussionsupporting

confidence: 61%

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Molecular characterization reveals genomic and transcriptomic subtypes of metastatic urothelial carcinoma

Nakauma-González

Rijnders

Riet

et al. 2021

Preprint

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Metastatic urothelial carcinoma (mUC) is a lethal cancer for which few therapeutic options exist. To define the molecular landscape of mUC and to identify targets for therapy, we performed whole genome DNA- and RNA-sequencing on fresh-frozen metastatic tumor biopsies of 116 mUC patients. Driver genes resembled those reported for primary UC; yet, three putative driver genes unique to mUC were identified: CNTNAP5, RARG and MGP. Consensus clustering based on mutational signatures revealed two major genomic subtypes. The most prevalent subtype (67%) consisted almost exclusively of tumors with high APOBEC mutagenesis. Five RNA-based subtypes were identified, of which four resembled those reported for primary UC, and one had a non-specified phenotype. By integrating the genomic and transcriptomic data potential therapeutic options per subtype and individual patient are proposed. This study serves as a reference for subtype-oriented and patient-specific research on the etiology of mUC, and for novel drug development.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionsupporting

confidence: 61%

Molecular characterization reveals genomic and transcriptomic subtypes of metastatic urothelial carcinoma

Nakauma-González

Rijnders

Riet

et al. 2021

Preprint

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“…To compare the results in the Neo-cohort to external data sets, we used the two largest datasets available; i) the Seiler et al study 12 with 190 cases meeting our inclusion criteria (Supplementary Figure 7), and ii) the Taber et al study 10 using the 96 cases with RNA-sequencing data (Supplementary Figure 8). While tumors classified as GU in the Seiler cohort had the largest proportion of pCR (47%) among the three major subtypes, it was not significantly different from that of Ba/Sq (44%) (Table 3).…”

Section: Resultsmentioning

confidence: 99%

“…The normalized gene expression matrix and clinical response data for the study by Taber and colleagues was retrieved from the supplementary data. 10 Of the 96 patients used, 21 were treated with neoadjuvant chemotherapy and 75 were treated with first line cisplatin-based chemotherapy in the metastatic setting. Single-sample LundTax classification of tumor samples from external cohorts (Seiler, n=190 and Taber, n=96) was performed on normalized but uncentered expression data.…”

Section: Methodsmentioning

confidence: 99%

Different responses to neoadjuvant chemotherapy in urothelial carcinoma molecular subtypes

Sjödahl

Abrahamsson

Holmsten

et al. 2021

Preprint

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For muscle-invasive bladder cancer (MIBC), there are no tissue biomarkers in clinical use that identify patients sensitive or resistant to neoadjuvant chemotherapy. The present study investigates how molecular subtypes impact pathological response and survival in 149 patients receiving preoperative cisplatin-based chemotherapy. Tumor classification was performed by transcriptomic profiling and by a 13-marker immunostaining panel. Furthermore, we explored differential gene expression and chemotherapy response beyond molecular subtypes. Tumors with Genomically Unstable (GU) and Urothelial-like (Uro) subtypes had higher proportions of pathological response and superior survival outcomes as compared to the Basal-Squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Based on our findings, we suggest that urothelial cancer of the luminal-like GU- and Uro-subtypes are more responsive to cisplatin-based chemotherapy. We also found the gene coding for osteopontin (SPP1) to display a subtype-dependent effect on chemotherapy response, confirmed at the protein level by immunohistochemistry. Combined analyses of second-generation, subtype-specific biomarkers may be an additional way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC.

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“…TME plays a regulatory role in tumorigenesis and in the interactions between cancer cells and surrounding components (such as cancer-associated broblasts, tumor-associated macrophages and tumor-associated lymphocyte), which promotes tumor development and metastasis [10,11]. Immune and stromal cells are the most abundant cell types and their degree of in ltration in the TME has a clinical prognostic value in many cancer types [12]. Therefore, a deeper understanding of the cell components (including immune cells and stromal cells) and the immunosuppressive status of the TME is critical to improving the e cacy of immunotherapy in cancers [13].…”

Section: Introductionmentioning

confidence: 99%

Identification of An Immune-related Signature in Predicting Prognosis of Oral Squamous Cell Carcinoma Patients

Li¹,

Meng²,

Chen³

et al. 2021

Preprint

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Background: Immunotherapy is one of the most promising treatment strategies in cancer, including oral squamous cell carcinoma (OSCC). This study aims to identify an immune-related signature to predict clinical outcomes of OSCC patients. Methods: Gene transcriptome data of OSCC tumour and normal tissues and corresponding clinical information were downloaded from The Cancer Genome Atlas (TCGA). Tumor Immune Estimation Resource algorithm (ESTIMATE) was used to calculate the immune/stromal-related scores. The immune/stromal scores and associated clinical characteristics of OSCC patients were evaluated. Univariate Cox proportional hazards regression analyses, least absolute shrinkage, and selection operator (LASSO) and receiver operating characteristic (ROC) curve analyses were performed to assess the prognostic prediction capacity. Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO) function annotation were used to analysis the functions of TME related genes.Results: 11 predictor genes were identified in the immune-related signature and overall survival (OS) in the high-risk group significantly shorter than the low-risk group. ROC analysis showed the TME related signature has well ability of predicting the total OS of OSCC patients. What’s more, GSEA and GO function annotation proved that immunity and immune-related pathways are mainly enriched in the high-risk group.Conclusions: We identified an immune-related signature that was closely correlated with the prognosis and immune response to OSCC patients. This signature may have important implications for improving the clinical survival rate of OSCC patients and provide a potential strategy for cancer immunotherapy.

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Molecular Correlates of Cisplatin-based Chemotherapy Response in Muscle Invasive Bladder Cancer by Integrated Multi-omics Analysis

Cited by 23 publications

References 0 publications

Molecular characterization reveals genomic and transcriptomic subtypes of metastatic urothelial carcinoma

Molecular characterization reveals genomic and transcriptomic subtypes of metastatic urothelial carcinoma

Different responses to neoadjuvant chemotherapy in urothelial carcinoma molecular subtypes

Identification of An Immune-related Signature in Predicting Prognosis of Oral Squamous Cell Carcinoma Patients

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