Abstract
Non-muscle invasive bladder cancer (NMIBC) represents a crucial problem for the national health care systems due to its high rates of recurrence and the consequent need of frequent follow-ups. Here, gene expression analyses in patients diagnosed as NMIBC were performed to determine those molecular pathways involved in tumor initiation, finding that both MYC and E2F are up regulated and helps to tumor initiation and progression. Our results also support an important involvement of alternative splicing events, modifying key pathways to favour bladder tumor evolution. Finally, since MDM2 showed differential exon usage, mutations in TP53 and its protein expression have been also studied in the same patients. Our data support that recurrence is epigenetically mediated and favoured by an increase protein expression of TP53, which appears more frequently mutated in advanced stages and grades, being associated to a worse prognosis. Therefore, TP53 mutational status could be used as a potential biomarker in the first stages of NMIBC to predict recurrence and prognosis.
Highlights
IntroductionDifferent transcriptomic technologies, it is possible to study gene expression at the exon resolution, allowing the detection of AS events that could be altering cancer key pathways
Expression of genes differentially expressed was compared to those gene-sets included in the Oncogenic Molecular Signatures Database (MSigDB) frequently deregulated in cancer
We found that genes with differential expression matched with signatures of key oncogenic pathways such as those upregulated by Shh stimulation, MYC overexpression, E2F1 upregulation, or by Rb1-Rbl[2] ablation (Fig. 1C)
Summary
Different transcriptomic technologies, it is possible to study gene expression at the exon resolution, allowing the detection of AS events that could be altering cancer key pathways. Different associations between particular AS events and patient prognosis have been reported in several tumor types[8,9], little is still known in the case of BC10–12. Our results support a key role of AS able of modulating expression of crucial pathways, favouring tumor progression. Following the results found, single nucleotide variations in TP53 gene were analysed using Generation Sequencing. This is especially interesting since TP53 has been frequently detected as mutated and related to chemo-resistance in MIBC13–16, but its role and status in NMIBC is still to be clarified.
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