Molecular characterization of neuroendocrine-like bladder cancer

Costa, Jane; Gibb, E.A.; Bivalacqua, Trinity J.; Liu, Y.; Oo, H.Z.; Miyamoto, Daisei; Alshalalfa, Mohamed; Davicioni, Elai; Wright, Jay; Dall′Era, Marc; Douglas, J.; Boormans, L.; Heijden, Michiel S. van der; Wu, CL; Gupta, Shubha; Grivas, Petros; Mouw, Kent W.; Konety, B.R.; Seiler, Roland; Daneshmand, Sia; Mian, Omar Y.; Efstathiou, J.A.; Lotan, Yair; Black, P.

doi:10.1016/s1569-9056(19)30464-6

Cited by 13 publications

(13 citation statements)

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“…Multiple strategies for molecular classification of UBCs have been reported 5 , 6 , 8 - 10 , 37 . Molecular subtypes, including luminal, basal, squamous-differentiation, epithelial-mesenchymal, cancer-stem cell, Claudin-low, p53-like, and neuroendocrine, started to be used for predictions of clinical outcomes and therapeutic interventions.…”

Section: Discussionmentioning

confidence: 99%

“…The intratumoral and intertumoral heterogeneity at the genomic, transcriptional and cellular levels contribute to the capricious outcomes of UBC patients 4 . Even the pathologically similar, the intrinsic molecular and genetic events were quite different; thus, a number of groups used gene expression patterns to reveal the molecular subtypes which traverse stage and grade classification 5 - 10 . For MIBCs, the luminal-like subtype was characterized by the expression of transcription factors and markers for differentiation (GATA3, FoxA1 and KRT20) 11 , 12 ; whereas, the basal-like subtype was enriched with cancer stem cell, mesenchymal-like markers (KRT14, KRT5, CD44, and Snails) and squamous differentiation markers (TGM1 and PI3) 9 .…”

Section: Introductionmentioning

confidence: 99%

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Identification of glycogene-type and validation of ST3GAL6 as a biomarker predicts clinical outcome and cancer cell invasion in urinary bladder cancer

Dalangood

Zhu

et al. 2020

Theranostics

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Background: Urinary bladder cancer (UBC) is one of the most common causes of morbidity and mortality worldwide characterized by a high risk of invasion and metastasis; however, the molecular classification biomarkers and underlying molecular mechanisms for UBC patient stratification on clinical outcome need to be investigated. Methods: A systematic transcriptomic analysis of 185 glycogenes in the public UBC datasets with survival information and clinicopathological parameters were performed using unsupervised hierarchical clustering. The gene signature for glycogene-type classification was identified using Limma package in R language, and correlated to 8 known molecular features by Gene Set Variation Analysis (GSVA). The clinical relevance and function of a glycogene was characterized by immunohistochemistry in UBC patient samples, and quantitative RT-PCR, Western blotting, promoter activity, MAL II blotting, immunofluorescence staining, wound healing, and transwell assays in UBC cells. Results: A 14-glycogene signature for glycogene-type classification was identified. Among them, ST3GAL6, a glycotransferase to transfer sialic acid to 3'-hydroxyl group of a galactose residue, showed a significant negative association with the subtype with luminal feature in UBC patients (n=2,130 in total). Increased ST3GAL6 was positively correlated to tumor stage, grade, and survival in UBCs from public datasets or our cohort (n=52). Transcription factor GATA3, a luminal-specific marker for UBC, was further identified as a direct upstream regulator of ST3GAL6 to negatively regulate its transactivation. ST3GAL6 depletion decreased MAL II level, cell invasion and migration in 5637 and J82 UBC cells. ST3GAL6 could reverse the effects of GATA3 on global sialylation and cell invasion in SW780 cells. Conclusions: Herein, we successfully identified a novel 14-gene signature for glycogene-type classification of UBC patients. ST3GAL6 gene, from this signature, was demonstrated as a potential biomarker for poor outcomes and cell invasion in UBCs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of glycogene-type and validation of ST3GAL6 as a biomarker predicts clinical outcome and cancer cell invasion in urinary bladder cancer

Dalangood

Zhu

et al. 2020

Theranostics

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“…This classifier was then tested on a cystectomy set and identified cases with transcriptome-level neuroendocrine features, which lacked specific neuroendocrine morphology (neuroendocrine-like tumors.) The neuroendocrinelike cases showed poor overall survival, consistent with the aggressive behavior of neuroendocrine carcinoma [80]. Validation of this neuroendocrine classifier in a subsequent study supported its ability to identify neuroendocrine-like tumors, with the need to manage these tumors similar to morphologically apparent neuroendocrine carcinomas [81].…”

Section: Neuroendocrine Carcinomamentioning

confidence: 63%

Histologic Variants of Urothelial Carcinoma: Morphology, Molecular Features and Clinical Implications

Alderson

Grivas

Milowsky

et al. 2020

BLC

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Bladder cancer is a heterogeneous disease including conventional urothelial carcinoma (UC) and its histologic variants, and non-urothelial carcinoma, including squamous and glandular neoplasms. Urothelial carcinoma accounts for the majority of bladder cancer cases, but morphologic variants are common and include nested, microcystic, micropapillary, lymphoepithelioma-like, plasmacytoid, sarcomatoid, giant cell, undifferentiated, clear cell and lipoid. Certain variants of UC tend to be associated with a poor prognosis and have diagnostic and potential treatment implications that make the identification of variant histology crucial to clinical decision making. While there is still uncertainty regarding the prognostic implications of many of these variants, identifying and reporting variant histology is important to develop our understanding of their biology. Unique molecular features accompany many of these morphologic variants and to better understand these tumors, we review the molecular and clinical implications of histologic variants of bladder cancer. Major efforts are underway to include variant histology and divergent differentiation of UC in clinical trials to develop evidence based approaches to treatment. The purpose of this article is to review the current literature on variant histology of urothelial cancer and to highlight molecular findings and the clinical relevance of these tumors.

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“…Despite the lowest survival rates, there are not yet available specific treatment options for neuronal bladder cancer. Current treatment regimens mostly consist of neoadjuvant chemotherapy combined with radical cystectomy or radiotherapy 56 . Thus, development of specific treatment strategies for neuronal type bladder cancer is essential.…”

Section: Discussionmentioning

confidence: 99%

Analysis of open chromatin regions in bladder cancer links β-catenin mutations and Wnt signaling with neuronal subtype of bladder cancer

Eray¹,

Güneri

Yılmaz³

et al. 2020

Sci Rep

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Urothelial carcinoma of the bladder is the most frequent bladder cancer affecting more than 400,000 people each year. Histopathologically, it is mainly characterized as muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC). Recently, the studies largely driven by consortiums such as TCGA identified the mutational landscape of both MIBC and NMIBC and determined the molecular subtypes of bladder cancer. Because of the exceptionally high rate of mutations in chromatin proteins, bladder cancer is thought to be a disease of chromatin, pointing out to the importance of studying epigenetic deregulation and the regulatory landscape of this cancer. In this study, we have analyzed ATAC-seq data generated for MIBC and integrated our findings with gene expression and DNA methylation data to identify subgroup specific regulatory patterns for MIBC. Our computational analysis revealed three MIBC regulatory clusters, which we named as neuronal, non-neuronal and luminal outlier. We have identified target genes of neuronal regulatory elements to be involved in WNT signaling, while target genes of non-neuronal and luminal outlier regulatory regions were enriched in epithelial differentiation and drug metabolism, respectively. Neuronal regulatory elements were determined to be ß-catenin targets (p value = 3.59e−08) consisting of genes involved in neurogenesis such as FGF9, and PROX1, and significantly enriched for TCF/LEF binding sites (p value = 1e−584). Our results showed upregulation of ß-catenin targets regulated by neuronal regulatory elements in three different cohorts, implicating ß-catenin signature in neuronal bladder cancer. Further, integration with mutation data revealed significantly higher oncogenic exon 3 ß-catenin mutations in neuronal bladder cancer compared to non-neuronal (odds ratio = 31.33, p value = 1.786e−05). Our results for the first time identify regulatory elements characterizing neuronal bladder cancer and links these neuronal regulatory elements with WNT signaling via mutations in β-catenin and its destruction complex components.

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Molecular characterization of neuroendocrine-like bladder cancer

Cited by 13 publications

References 0 publications

Identification of glycogene-type and validation of ST3GAL6 as a biomarker predicts clinical outcome and cancer cell invasion in urinary bladder cancer

Identification of glycogene-type and validation of ST3GAL6 as a biomarker predicts clinical outcome and cancer cell invasion in urinary bladder cancer

Histologic Variants of Urothelial Carcinoma: Morphology, Molecular Features and Clinical Implications

Analysis of open chromatin regions in bladder cancer links β-catenin mutations and Wnt signaling with neuronal subtype of bladder cancer

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