Abstract 3828: Genomic, transcriptome and epigenomic analysis reveal new genetic pathways in penile carcinoma

Background: Penile carcinoma (PeCa) is a rare and high morbidity disease. In contrast with other urological neoplasia, there is a paucity of molecular and epigenetic data in PeCa. By using integrative genetic, epigenetic and transcriptome analysis the main aim was to identify molecular drivers in PeCa. Patients and Methods: 37 PeCa samples, 16 surrounding normal tissues and 14 normal glands were used for evaluate DNA methylation status (244K Human DNA Methylation Microarray platform, Agilent Technologies), large-scale expression (4×44K Whole Human Genome Microarray, Agilent Technologies and GeneChip® Human Transcriptome Array 2.0, Affymetrix), miRNA expression (TaqMan Human MicroRNA Array v2.0, Applied Biosystems) and genomic copy number alterations by array-CGH (Agilent Human 4×44K CGH Microarrays, Agilent Technologies). Quantitative bisulfite pyrosequencing (qBP), qPCR and RT-qPCR were used to validate the findings in an independent set of samples. HPV status was assessed using the Linear Array HPV Genotyping kit (Roche Molecular Diagnostics, CA, USA). IPA (Ingenuity Pathways Analysis) and KOBAS software were used for network analysis. Results: HPV positivity was detected in 32% of cases, mainly for HPV16 subtype. Gain of 8q (66% of cases), where MYC gene (8q24) is mapped, was de main alteration detected by array-CGH. Gene expression profiles from both Agilent and Affymetrix microarrays identified overexpression of matrix metalloprotease and keratin gene families in tumor samples. Integrative analysis between methylome and transcriptome revealed a panel of 70 genes with inverse correlation between methylation and gene expression. Genes reported in stem cell regulation (SOX family and WNT pathway genes) were altered, suggesting the involvement of stem cells in a subset of PeCa. Concurrent CpG hypermetlylation and down-expression was confirmed in 30 genes/miRNAs. Transcriptome, methylome and miRNA profiles distinguished PeCa cases according to HPV status. Particularly, down-regulation of hsa-miR-29 family members was confirmed in HPV-positive tumors. Conclusion: These findings suggest that deregulation of pathways related to transcriptional regulation of stem cells, matrix metalloprotease, MYC amplification and hsa-miR-29 family disruption are involved in penile carcinogenesis. Financial support: FAPESP (2013/03667-6) and CNPq Citation Format: Hellen Kuasne, Fabio A. Marchi, Ariane F. Busso, Mateus C. Barros-Filho, Juan JAM Munoz, Hector Hernandez-Vargas, Cristovam Scapulatempo-Neto, Eliney F. Faria, Ademar Lopes, Gustavo C. Guimaraes, Jose C. Trindade-Filho, Zdenko Herceg, Silvia R. Rogatto. Genomic, transcriptome and epigenomic analysis reveal new genetic pathways in penile carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3828. doi:10.1158/1538-7445.AM2015-3828