Abstract
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.
Highlights
Bladder cancer is one of the most common urologic malignancies with estimated 80,470 new cases and 17,670 new deaths in the United States in 2019 [1]
The primary aim of this study is to provide a method for a comprehensive molecular characterization of the 8q22.2 region in bladder cancer using in silico copy number alterations (CNA) and mRNA gene expression data
High OSR2 mRNA levels are associated with decreased disease-free survival (DFS) in silico and overall survival (OS) in RT-qPCR data, respectively, and could serve as a potential biomarker for muscle invasive bladder cancer (MIBC)
Summary
Bladder cancer is one of the most common urologic malignancies with estimated 80,470 new cases and 17,670 new deaths in the United States in 2019 [1]. Muscle invasive bladder cancer (MIBC) is associated with a poor 5-year survival rate of 40–60% [2]. Technological advances in molecular profiling, such as highthroughput sequencing technologies, have augmented cytogenetic, fluorescence in situ hybridization (FISH) and array-comparative-genomic-hybridization (aCGH) studies. These results have created an additional complexity through the generation of an unprecedented series of copy number alterations (CNA) and mRNA gene expression data, in addition to classical oncogene mutations [3,4,5,6,7]. The complexity of this molecularly altered landscape and its potential interactions requires an in-depth comprehensive analysis and correlation with clinical phenotype and prognosis [8]
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