Using Copy Number Alterations to Identify New Therapeutic Targets for Bladder Carcinoma

Abstract

Bladder cancer represents the ninth most widespread malignancy throughout the world. It is characterized by the presence of two different clinical and prognostic subtypes: non-muscle-invasive bladder cancers (NMIBCs) and muscle-invasive bladder cancers (MIBCs). MIBCs have a poor outcome with a common progression to metastasis. Despite improvements in knowledge, treatment has not advanced significantly in recent years, with the absence of new therapeutic targets. Because of the limitations of current therapeutic options, the greater challenge will be to identify biomarkers for clinical application. For this reason, we compared our array comparative genomic hybridization (array-CGH) results with those reported in literature for invasive bladder tumors and, in particular, we focused on the evaluation of copy number alterations (CNAs) present in biopsies and retained in the corresponding cancer stem cell (CSC) subpopulations that should be the main target of therapy. According to our data, CCNE1, MYC, MDM2 and PPARG genes could be interesting therapeutic targets for bladder CSC subpopulations. Surprisingly, HER2 copy number gains are not retained in bladder CSCs, making the gene-targeted therapy less interesting than the others. These results provide precious advice for further study on bladder therapy; however, the clinical importance of these results should be explored.

Keywords: bladder cancer; cancer stem cells; copy number alterations; therapeutic targets; transitional cell carcinomas.

Figure 1

Examples of fluorescence in situ hybridization (FISH) analysis on formalin-fixed, paraffin-embedded (FFPE) tissues on the same tumoral area (case 27): (a) Her-2/Neu (17q12)/SE17 (SE: satellite enumeration) probe (human epidermal growth factor receptor 2 (HER2) red, centromere 17green); (b) PPARγ Break probe. Yellow dots represent the fusion of green and red signals of the dual color split probe.