title: Genome-wide methylation and transcriptome analysis in penile carcinoma: uncovering new molecular markers.
abstract: BACKGROUND
  Despite 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).
  
  
  RESULTS
  Genome-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.
  
  
  CONCLUSIONS
  A 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.
authors.affiliation: CIPE - International Research Center, AC Camargo Cancer Center, Rua Taguá, 440, CEP: 01508-010, Liberdade, São Paulo, SP Brazil ; Department of Biology, Londrina State University, Londrina, PR Brazil.
authors.forename: Hellen
authors.initials: H
authors.lastname: Kuasne
authors.affiliation: Department of Biology, Londrina State University, Londrina, PR Brazil.
authors.forename: Ilce Mara de Syllos
authors.initials: IM
authors.lastname: Cólus
authors.affiliation: CIPE - International Research Center, AC Camargo Cancer Center, Rua Taguá, 440, CEP: 01508-010, Liberdade, São Paulo, SP Brazil.
authors.forename: Ariane Fidelis
authors.initials: AF
authors.lastname: Busso
authors.affiliation: Epigenetics Group, International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Hector
authors.initials: H
authors.lastname: Hernandez-Vargas
authors.affiliation: CIPE - International Research Center, AC Camargo Cancer Center, Rua Taguá, 440, CEP: 01508-010, Liberdade, São Paulo, SP Brazil.
authors.forename: Mateus Camargo
authors.initials: MC
authors.lastname: Barros-Filho
authors.affiliation: CIPE - International Research Center, AC Camargo Cancer Center, Rua Taguá, 440, CEP: 01508-010, Liberdade, São Paulo, SP Brazil ; Inter-institutional Grad Program on Bioinformatics, Institute of Mathematics and Statistics, USP, São Paulo, SP Brazil.
authors.forename: Fabio Albuquerque
authors.initials: FA
authors.lastname: Marchi
authors.affiliation: Department of Pathology, CPOM - Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP Brazil.
authors.forename: Cristovam
authors.initials: C
authors.lastname: Scapulatempo-Neto
authors.affiliation: Department of Urology, Barretos Cancer Hospital, Barretos, SP Brazil.
authors.forename: Eliney Ferreira
authors.initials: EF
authors.lastname: Faria
authors.affiliation: Department of Pelvic Surgery, AC Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Ademar
authors.initials: A
authors.lastname: Lopes
authors.affiliation: Department of Pelvic Surgery, AC Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Gustavo Cardoso
authors.initials: GC
authors.lastname: Guimarães
authors.affiliation: Epigenetics Group, International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Herceg
authors.affiliation: CIPE - International Research Center, AC Camargo Cancer Center, Rua Taguá, 440, CEP: 01508-010, Liberdade, São Paulo, SP Brazil ; Department of Urology, Faculty of Medicine, UNESP, Botucatu, SP Brazil.
authors.forename: Silvia Regina
authors.initials: SR
authors.lastname: Rogatto
keywords: DNA methylome; Human papillomavirus; Molecular marker; Penile carcinomas; Transcriptome