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Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets.

ABSTRACT: BACKGROUND:Molecular characterization of nonmuscle invasive bladder cancer (NMIBC) may provide a biologic rationale for treatment response and novel therapeutic strategies. OBJECTIVE:To identify genetic alterations with potential clinical implications in NMIBC. DESIGN, SETTING, AND PARTICIPANTS:Pretreatment index tumors and matched germline DNA from 105 patients with NMIBC on a prospective Institutional Review Board-approved protocol underwent targeted exon sequencing analysis in a Clinical Laboratory Improvement Amendments-certified clinical laboratory. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Comutation patterns and copy number alterations were compared across stage and grade. Associations between genomic alterations and recurrence after intravesical bacillus Calmette-Guérin (BCG) were estimated using Kaplan-Meier and Cox regression analyses. RESULTS AND LIMITATIONS:TERT promoter mutations (73%) and chromatin-modifying gene alterations (69%) were highly prevalent across grade and stage, suggesting these events occur early in tumorigenesis. ERBB2 or FGFR3 alterations were present in 57% of high-grade NMIBC tumors in a mutually exclusive pattern. DNA damage repair (DDR) gene alterations were seen in 30% (25/82) of high-grade NMIBC tumors, a rate similar to MIBC, and were associated with a higher mutational burden compared with tumors with intact DDR genes (p<0.001). ARID1A mutations were associated with an increased risk of recurrence after BCG (hazard ratio=3.14, 95% confidence interval: 1.51-6.51, p=0.002). CONCLUSIONS:Next-generation sequencing of treatment-naive index NMIBC tumors demonstrated that the majority of NMIBC tumors had at least one potentially actionable alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy. DDR gene alterations were frequent in high-grade NMIBC and were associated with increased mutational load, which may have therapeutic implications for BCG immunotherapy and ongoing trials of systemic checkpoint inhibitors. ARID1A mutations were associated with an increased risk of recurrence after BCG therapy. Whether ARID1A mutations represent a predictive biomarker of BCG response or are prognostic in NMIBC patients warrants further investigation. PATIENT SUMMARY:Analysis of frequently mutated genes in superficial bladder cancer suggests potential targets for personalized treatment and predictors of treatment response, and also may help develop noninvasive tumor detection tests.

SUBMITTER: Pietzak EJ

PROVIDER: S-EPMC6007852 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets.

Pietzak Eugene J EJ Bagrodia Aditya A Cha Eugene K EK Drill Esther N EN Iyer Gopa G Isharwal Sumit S Ostrovnaya Irina I Baez Priscilla P Li Qiang Q Berger Michael F MF Zehir Ahmet A Schultz Nikolaus N Rosenberg Jonathan E JE Bajorin Dean F DF Dalbagni Guido G Al-Ahmadie Hikmat H Solit David B DB Bochner Bernard H BH

European urology 20170603 6

<h4>Background</h4>Molecular characterization of nonmuscle invasive bladder cancer (NMIBC) may provide a biologic rationale for treatment response and novel therapeutic strategies.<h4>Objective</h4>To identify genetic alterations with potential clinical implications in NMIBC.<h4>Design, setting, and participants</h4>Pretreatment index tumors and matched germline DNA from 105 patients with NMIBC on a prospective Institutional Review Board-approved protocol underwent targeted exon sequencing analy ...[more]

PMID: 28583311

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Project description:BackgroundHeart failure (HF) is the most common cardiovascular diseases and the leading cause of cardiovascular diseases related deaths. Increasing molecular targets have been discovered for HF prognosis and therapy. However, there is still an urgent need to identify novel biomarkers. Therefore, we evaluated biomarkers that might aid the diagnosis and treatment of HF.MethodsWe searched next-generation sequencing (NGS) dataset (GSE161472) and identified differentially expressed genes (DEGs) by comparing 47 HF samples and 37 normal control samples using limma in R package. Gene ontology (GO) and pathway enrichment analyses of the DEGs were performed using the g: Profiler database. The protein-protein interaction (PPI) network was plotted with Human Integrated Protein-Protein Interaction rEference (HiPPIE) and visualized using Cytoscape. Module analysis of the PPI network was done using PEWCC1. Then, miRNA-hub gene regulatory network and TF-hub gene regulatory network were constructed by Cytoscape software. Finally, we performed receiver operating characteristic (ROC) curve analysis to predict the diagnostic effectiveness of the hub genes.ResultsA total of 930 DEGs, 464 upregulated genes and 466 downregulated genes, were identified in HF. GO and REACTOME pathway enrichment results showed that DEGs mainly enriched in localization, small molecule metabolic process, SARS-CoV infections, and the citric acid tricarboxylic acid (TCA) cycle and respiratory electron transport. After combining the results of the PPI network miRNA-hub gene regulatory network and TF-hub gene regulatory network, 10 hub genes were selected, including heat shock protein 90 alpha family class A member 1 (HSP90AA1), arrestin beta 2 (ARRB2), myosin heavy chain 9 (MYH9), heat shock protein 90 alpha family class B member 1 (HSP90AB1), filamin A (FLNA), epidermal growth factor receptor (EGFR), phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), cullin 4A (CUL4A), YEATS domain containing 4 (YEATS4), and lysine acetyltransferase 2B (KAT2B).ConclusionsThis discovery-driven study might be useful to provide a novel insight into the diagnosis and treatment of HF. However, more experiments are needed in the future to investigate the functional roles of these genes in HF.

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Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets.

Publications

Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets.

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