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Clinical Epigenetics

, 7:46

First Online: 18 April 2015Received: 30 October 2014Accepted: 06 April 2015


BackgroundDespite penile carcinoma PeCa being a relatively rare neoplasm, it remains an important public health issue for poor and developing countries. Contrary to most tumors, limited data are available for markers that are capable of assisting in diagnosis, prognosis, and treatment of PeCa. We aimed to identify molecular markers for PeCa by evaluating their epigenomic and transcriptome profiles and comparing them with surrounding non-malignant tissue SNT and normal glans NG.

ResultsGenome-wide methylation analysis revealed 171 hypermethylated probes in PeCa. Transcriptome profiling presented 2,883 underexpressed and 1,378 overexpressed genes. Integrative analysis revealed a panel of 54 genes with an inverse correlation between methylation and gene expression levels. Distinct methylome and transcriptome patterns were found for human papillomavirus HPV-positive 38.6% and negative tumors. Interestingly, grade 3 tumors showed a distinct methylation profile when compared to grade 1. In addition, univariate analysis revealed that low BDNF methylation was associated with lymph node metastasis and shorter disease-free survival. CpG hypermethylation and gene underexpression were confirmed for a panel of genes, including TWIST1, RSOP2, SOX3, SOX17, PROM1, OTX2, HOXA3, and MEIS1.

ConclusionsA unique methylome signature was found for PeCa compared to SNT, with aberrant DNA methylation appearing to modulate the expression of specific genes. This study describes new pathways with the potential to regulate penile carcinogenesis, including stem cell regulatory pathways and markers associated to a worse prognosis. These findings may be instrumental in the discovery and application of new genetic and epigenetic biomarkers in PeCa.

KeywordsPenile carcinomas DNA methylome Human papillomavirus Molecular marker Transcriptome AbbreviationsCIConfidence interval

FDRFalse discovery rate

HCLHierarchical clustering analysis

IPAIngenuity pathway analysis

GSEAGene set enrichment analysis

KOBASKEGG orthology based annotation system

MCIpMethyl-CpG immunoprecipitation

MMPsMatrix metalloproteinases

NGNormal glans

PeCaPenile carcinoma

SNTSurrounding non-malignant tissues

HPVHuman papillomavirus

Electronic supplementary materialThe online version of this article doi:10.1186-s13148-015-0082-4 contains supplementary material, which is available to authorized users.

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Autor: Hellen Kuasne - Ilce Mara de Syllos Cólus - Ariane Fidelis Busso - Hector Hernandez-Vargas - Mateus Camargo Barros-Filh


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