Multidimensional integrative analysis uncovers driver candidates and biomarkers in penile carcinoma

Abstract

Molecular data generation and their combination in penile carcinomas (PeCa), a significant public health problem in poor and underdeveloped countries, remain virtually unexplored. An integrativemethodology combin ing genome-wide copy number alteration, DNA methylation, miRNA and mRNA expression analysis was performed in a set of 20 usual PeCa. The well-ranked 16 driver candidates harboring genomic alterations and regulated by a set of miRNAs, including hsa-miR-31, hsa-miR-34a and hsa-miR-130b, were significantly associated with over-represented pathways in cancer, such as immune-inflammatory system, apoptosis and cell cycle. Modules of co-expressed genes generated from expression matrix were associated with driver candidates and classified according to the over-representation of passengers, thus suggesting an alteration of the pathway dynamics during the carcinogenesis. This association resulted in 10 top driver candidates (AR, BIRC5, DNMT3B, ERBB4, FGFR1, PML, PPARG, RB1, TNFSF10 and STAT1) selected and confirmed as altered in an independent set of 33 PeCa samples. In addition to the potential driver genes herein described, shorter overall survival was associated with BIRC5 and DNMT3B overexpression (log-rank test, P = 0.026 and P = 0.002, respectively) highlighting its potential as novel prognostic marker for penile cancer.

Nuclear loss and cytoplasmic expression of androgen receptor in penile carcinomas: role as a driver event and as a prognosis factor

“…Androgen receptor has been described as a major oncogenic driver in prostate cancer [9]. In penile tumors, the AR gene was one of the top 10 putative drivers involved in genomic loss and regulated by oncomiRs, which was a plausible explanation for the mRNA lower expression levels [28]. In parallel, we showed that AR is at least 30 folds down-expressed in PeCa compared to normal tissues giving additional support for the involvement of this gene in penile carcinogenesis [19].…”

“…Molecular alterations in PeCa have been described only recently by our group and others [19,[21][22][23][24][25][26][27][28][29][30]. Interestingly, contrary to the findings described in breast and prostate cancers, AR mRNA is down-expressed in PeCa [19].…”

“…Interestingly, contrary to the findings described in breast and prostate cancers, AR mRNA is down-expressed in PeCa [19]. Moreover, AR alteration was pointed out as one of the main putative drivers in PeCa [28]. The molecular mechanism leading to AR down-expression in PeCa is poorly clarified.…”

“…The molecular mechanism leading to AR down-expression in PeCa is poorly clarified. Nonetheless, X chromosome loss [31], overexpression of microRNAs targeting the AR gene [19,28], and hypermethylation of the AR gene promoter [23] have been described as mechanisms leading to AR downregulation.…”

TGF-β and microRNA Interplay in Genitourinary Cancers

“…Furthermore, TGFB3 and TGFBR2 were found within the top pathways involving miRNA-targeted genes disrupted in penile cancer [291]. TGFBR2 was also predicted as one of the 47 candidate driver genes targeted by multiple miRNAs, the expressions of which were altered in penile cancer samples compared with normal penile tissue [292]. None of these studies, however, included functional analysis to validate the miRNA-mediated regulation of TGF-β pathway genes, nor the TGF-β-mediated regulation of miRNAs.…”