Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer.
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ABSTRACT:
SUBMITTER: Robertson AG
PROVIDER: S-EPMC5687509 | biostudies-literature | 2017 Oct
REPOSITORIES: biostudies-literature
Publications
Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer.
Robertson A Gordon AG Kim Jaegil J Al-Ahmadie Hikmat H Bellmunt Joaquim J Guo Guangwu G Cherniack Andrew D AD Hinoue Toshinori T Laird Peter W PW Hoadley Katherine A KA Akbani Rehan R Castro Mauro A A MAA Gibb Ewan A EA Kanchi Rupa S RS Gordenin Dmitry A DA Shukla Sachet A SA Sanchez-Vega Francisco F Hansel Donna E DE Czerniak Bogdan A BA Reuter Victor E VE Su Xiaoping X de Sa Carvalho Benilton B Chagas Vinicius S VS Mungall Karen L KL Sadeghi Sara S Pedamallu Chandra Sekhar CS Lu Yiling Y Klimczak Leszek J LJ Zhang Jiexin J Choo Caleb C Ojesina Akinyemi I AI Bullman Susan S Leraas Kristen M KM Lichtenberg Tara M TM Wu Catherine J CJ Schultz Nicholaus N Getz Gad G Meyerson Matthew M Mills Gordon B GB McConkey David J DJ Weinstein John N JN Kwiatkowski David J DJ Lerner Seth P SP
Cell 20171005 3
We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked sm ...[more]
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Project description:Technological advances in molecular profiling have enabled the comprehensive identification of common regions of gene amplification on chromosomes (amplicons) in muscle invasive bladder cancer (MIBC). One such region is 8q22.2, which is largely unexplored in MIBC and could harbor genes with potential for outcome prediction or targeted therapy. To investigate the prognostic role of 8q22.2 and to compare different amplicon definitions, an in-silico analysis of 357 patients from The Cancer Genome Atlas, who underwent radical cystectomy for MIBC, was performed. Amplicons were generated using the GISTIC2.0 algorithm for copy number alterations (DNA_Amplicon) and z-score normalization for mRNA gene overexpression (RNA_Amplicon). Kaplan-Meier survival analysis, univariable, and multivariable Cox proportional hazard ratios were used to relate amplicons, genes, and clinical parameters to overall (OS) and disease-free survival (DFS). Analyses of the biological functions of 8q22.2 genes and genomic events in MIBC were performed to identify potential targets. Genes with prognostic significance from the in silico analysis were validated using RT-qPCR of MIBC tumor samples (n = 46). High 8q22.2 mRNA expression (RNA-AMP) was associated with lymph node metastases. Furthermore, 8q22.2 DNA and RNA amplified patients were more likely to show a luminal subtype (DNA_Amplicon_core: p = 0.029; RNA_Amplicon_core: p = 0.01). Overexpression of the 8q22.2 gene OSR2 predicted shortened DFS in univariable (HR [CI] 1.97 [1.2; 3.22]; p = 0.01) and multivariable in silico analysis (HR [CI] 1.91 [1.15; 3.16]; p = 0.01) and decreased OS (HR [CI] 6.25 [1.37; 28.38]; p = 0.0177) in RT-qPCR data analysis. Alterations in different levels of the 8q22.2 region are associated with manifestation of different clinical characteristics in MIBC. An in-depth comprehensive molecular characterization of genomic regions involved in cancer should include multiple genetic levels, such as DNA copy number alterations and mRNA gene expression, and could lead to a better molecular understanding. In this study, OSR2 is identified as a potential biomarker for survival prognosis.
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Project description:BackgroundMuscle-invasive bladder cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, but the diversity of their subtype sets impedes their clinical application.ObjectiveTo achieve an international consensus on MIBC molecular subtypes that reconciles the published classification schemes.Design, setting, and participantsWe used 1750 MIBC transcriptomic profiles from 16 published datasets and two additional cohorts.Outcome measurements and statistical analysisWe performed a network-based analysis of six independent MIBC classification systems to identify a consensus set of molecular classes. Association with survival was assessed using multivariable Cox models.Results and limitationsWe report the results of an international effort to reach a consensus on MIBC molecular subtypes. We identified a consensus set of six molecular classes: luminal papillary (24%), luminal nonspecified (8%), luminal unstable (15%), stroma-rich (15%), basal/squamous (35%), and neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics, including outcomes. We provide a single-sample classifier that assigns a consensus class label to a tumor sample's transcriptome. Limitations of the work are retrospective clinical data collection and a lack of complete information regarding patient treatment.ConclusionsThis consensus system offers a robust framework that will enable testing and validation of predictive biomarkers in future prospective clinical trials.Patient summaryBladder cancers are heterogeneous at the molecular level, and scientists have proposed several classifications into sets of molecular classes. While these classifications may be useful to stratify patients for prognosis or response to treatment, a consensus classification would facilitate the clinical use of molecular classes. Conducted by multidisciplinary expert teams in the field, this study proposes such a consensus and provides a tool for applying the consensus classification in the clinical setting.
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