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      ANLN and TLE2 in Muscle Invasive Bladder Cancer: A Functional and Clinical Evaluation Based on In Silico and In Vitro Data

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          Abstract

          Anilin actin binding protein (ANLN) and transducing-like enhancer protein 2 (TLE2) are associated with cancer patient survival and progression. The impact of their gene expression on progression-free survival (PFS) of patients with muscle invasive bladder cancer (MIBC) treated with radical cystectomy (RC) and subtype association has not yet been investigated. qRT-PCR was used to measure the transcript levels of ANLN and TLE2 in the Mannheim cohort, and validated in silico by The Cancer Genome Atlas (TCGA) cohort. Uni- and multivariate Cox regression analyses identified predictors for disease-specific survival (DSS) and overall survival (OS). In the Mannheim cohort, tumors with high ANLN expression were associated with lower OS and DSS, while high TLE2 expression was associated with a favorable OS. The TCGA cohort confirmed that high ANLN and low TLE2 expression was associated with shorter OS and disease-free survival (DFS). In both cohorts, multivariate analyses showed ANLN and TLE2 expression as independent outcome predictors. Furthermore, ANLN was more highly expressed in cell lines and patients with the basal subtype, while TLE2 expression was higher in cell lines and patients with the luminal subtype. ANLN and TLE2 are promising biomarkers for individualized bladder cancer therapy including cancer subclassification and informed MIBC prognosis.

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          Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology.

          We sought to define whether there are intrinsic molecular subtypes of high-grade bladder cancer. Consensus clustering performed on gene expression data from a meta-dataset of high-grade, muscle-invasive bladder tumors identified two intrinsic, molecular subsets of high-grade bladder cancer, termed "luminal" and "basal-like," which have characteristics of different stages of urothelial differentiation, reflect the luminal and basal-like molecular subtypes of breast cancer, and have clinically meaningful differences in outcome. A gene set predictor, bladder cancer analysis of subtypes by gene expression (BASE47) was defined by prediction analysis of microarrays (PAM) and accurately classifies the subtypes. Our data demonstrate that there are at least two molecularly and clinically distinct subtypes of high-grade bladder cancer and validate the BASE47 as a subtype predictor. Future studies exploring the predictive value of the BASE47 subtypes for standard of care bladder cancer therapies, as well as novel subtype-specific therapies, will be of interest.
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            Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma

            Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.
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              Updates in the Eighth Edition of the Tumor-Node-Metastasis Staging Classification for Urologic Cancers

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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                21 November 2019
                December 2019
                : 11
                : 12
                : 1840
                Affiliations
                [1 ]Department of Urology and Urosurgery, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany; sheng.wu@ 123456medma.uni-heidelberg.de (S.W.); katja.nitschke@ 123456medma.uni-heidelberg.de (K.N.); jakob.heinkele@ 123456medma.uni-heidelberg.de (J.H.); thomas.worst@ 123456medma.uni-heidelberg.de (T.S.W.)
                [2 ]Institute of Pathology, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany; cleo-aron.weis@ 123456umm.de (C.-A.W.); stefan.porubsky@ 123456umm.de (S.P.)
                [3 ]Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, 91052 Erlangen, Germany; markus.eckstein@ 123456uk-erlangen.de
                Author notes
                [* ]Correspondence: philipp.erben@ 123456medma.uni-heidelberg.de ; Tel.: +49-621-383-1610
                Author information
                https://orcid.org/0000-0001-5429-126X
                https://orcid.org/0000-0002-7647-7265
                https://orcid.org/0000-0002-8279-7636
                Article
                cancers-11-01840
                10.3390/cancers11121840
                6966660
                31766561
                c20eeb7a-4a53-4fba-8cdc-38f8e50e577c
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 15 October 2019
                : 19 November 2019
                Categories
                Article

                muscle invasive bladder cancer,prognosis,biomarker,molecular subtype

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