title: Epigenetics markers of metastasis and HPV-induced tumorigenesis in penile cancer.
abstract: OBJECTIVE
  Penile cancer is a rare malignancy in the developed world with just more than 1,600 new cases diagnosed in the United States per year; however, the incidence is much higher in developing countries. Although HPV is known to contribute to tumorigenesis, little is known about the genetic or epigenetic alterations defining penile cancer.
  
  
  METHODS
  Using high-density genome-wide methylation arrays, we have identified epigenetic alterations associated with penile cancer. Q-MSP was used to validate lymph node metastasis markers in 50 cases. A total of 446 head and neck squamous cell carcinoma (HNSCC) and cervical squamous cell carcinoma (CESCC) samples were used to validate HPV-associated epigenetic alterations.
  
  
  RESULTS
  We defined 6,933 methylation variable positions (MVP) between normal and tumor tissue, which includes 997 hypermethylated differentially methylated regions associated with tumor supressor genes, including CDO1, AR1, and WT1. Analysis of penile cancer tumors identified a 4 gene epi-signature which accurately predicted lymph node metastasis in an independent cohort (AUC of 89%). Finally, we explored the epigenetic alterations associated with penile cancer HPV infection and defined a 30 loci lineage-independent HPV specific epi-signature which predicts HPV status and survival in independent HNSCC, CESC cohorts. Epi-signature-negative patients have a significantly worse overall survival [HNSCC P = 0.00073; 95% confidence interval (CI), 0.021-0.78; CESC P = 0.0094; HR = 3.91, 95% CI = 0.13-0.78], HPV epi-signature is a better predictor of survival than HPV status alone.
  
  
  CONCLUSIONS
  These data demonstrate for the first time genome-wide epigenetic events involved in an aggressive penile cancer phenotype and define the epigenetic alterations common across multiple HPV-driven malignancies.
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom. a.feber@ucl.ac.uk j.d.kelly@ucl.ac.uk.
authors.forename: Andrew
authors.initials: A
authors.lastname: Feber
authors.affiliation: Division of Surgery and Interventional Science, UCL Medical School, University College London, London, United Kingdom. Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Manit
authors.initials: M
authors.lastname: Arya
authors.affiliation: Division of Surgery and Interventional Science, UCL Medical School, University College London, London, United Kingdom.
authors.forename: Patricia
authors.initials: P
authors.lastname: de Winter
authors.affiliation: Division of Surgery and Interventional Science, UCL Medical School, University College London, London, United Kingdom.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Saqib
authors.affiliation: University College London Hospital, 250 Euston Road, London, United Kingdom.
authors.forename: Raj
authors.initials: R
authors.lastname: Nigam
authors.affiliation: University College London Hospital, 250 Euston Road, London, United Kingdom.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Malone
authors.affiliation: Division of Surgery and Interventional Science, UCL Medical School, University College London, London, United Kingdom.
authors.forename: Wei Shen
authors.initials: WS
authors.lastname: Tan
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Rodney
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lechner
authors.affiliation: Department of Histopathology, University College London Hospital, London, United Kingdom.
authors.forename: Alex
authors.initials: A
authors.lastname: Freeman
authors.affiliation: Department of Histopathology, University College London Hospital, London, United Kingdom.
authors.forename: Charles
authors.initials: C
authors.lastname: Jameson
authors.affiliation: Division of Surgery and Interventional Science, UCL Medical School, University College London, London, United Kingdom. University College London Hospital, 250 Euston Road, London, United Kingdom.
authors.forename: Asif
authors.initials: A
authors.lastname: Muneer
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom. Division of Surgery and Interventional Science, UCL Medical School, University College London, London, United Kingdom. a.feber@ucl.ac.uk j.d.kelly@ucl.ac.uk.
authors.forename: John D
authors.initials: JD
authors.lastname: Kelly
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002472:Cell Transformation, Viral / Q000235:genetics*; D016000:Cluster Analysis; D019295:Computational Biology; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D009362:Neoplasm Metastasis; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000150:complications*; D010412:Penile Neoplasms / Q000209:etiology* / Q000473:pathology*; D012091:Repetitive Sequences, Nucleic Acid