Multidimensional integrative analysis uncovers driver candidates and biomarkers in penile carcinoma

Fabio Albuquerque Marchi,Ariane Fidelis Busso Lopes,David Correa Martins,Jose Carlos Souza Trindade Filho,Helena Brentani,Ademar Lopes,Hellen Kuasne,Gustavo Cardoso Guimarães,Mateus Camargo Barros-Filho,Cristovam Scapulatempo-Neto,Silvia Regina Rogatto,Eliney F Faria

doi:10.1038/s41598-017-06659-1

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.

Highlights

Molecular data generation and their combination in penile carcinomas (PeCa), a significant public health problem in poor and underdeveloped countries, remain virtually unexplored
By integrating methylome and gene expression data, we described a panel of 54 genes with inverse correlation, pointing out driver epigenetic events associated with dysregulated pathways in PeCa, such as stem cells, Wnt/β-catenin signaling and cell cycle[21]
The 47 driver candidates presented significant copy number alterations, with frequency varying from 35% to 90% of cases, 17 (36%) of them presented expression levels regulated by methylation, with a predominance of hypermethylation (16 of 47 genes)

Summary

Introduction

Molecular data generation and their combination in penile carcinomas (PeCa), a significant public health problem in poor and underdeveloped countries, remain virtually unexplored. More recently, the accumulation of deleterious passengers has been suggested as being associated with carcinogenesis, leading to an immune response and cellular stress, as well as contributing to therapy-resistance[3, 4] The identification of these biomarkers is hampered by genome complexity and limited investigation at a molecular level, which does not allow a broad overview of the different mechanisms involved in gene activity[5]. In order to overcome this issue, the combination of different molecular alterations in a comprehensive manner has been explored as a mechanism to reveal potential gene candidates associated with targeted pathways by therapeutic agents[6] Recent initiatives, such as TCGA (The Cancer Genome Atlas) and ICGC (International Cancer Genome Consortium), rendered novel insights on cancer system biology compared with isolated events[7]. Novel targeted-genes for cancer therapy have been described, there is a lack of studies generating and combining molecular data of penile carcinomas

Methods

Results

Conclusion