Purpose: Penile cancer is a rare malignancy in the developed world, with just over 1600 new cases diagnosed in the USA per year, however, the incidence is much higher in developing countries.
Although HPV is known to contribute to tumourigenesis, little is known about the genetic or epigenetic alterations defining penile cancer (PeCa).
Experimental Design: Using high-density genome-wide methylation arrays we have identified epigenetic alterations associated with PeCa. Q-MSP was used to validate lymph node metastasis markers in 50 cases. 446 HNSCC and CESCC (head and neck squamous cell carcinoma and cervical squamous cell carcinoma) samples were used to validate HPV associated epigenetic alterations.
Results: We defined 6933 methylation variable positions (MVPs) between normal and tumour tissue, which include 997 hypermethylated differentially methylated regions associated with tumour supressor genes including CDO1, AR1 and WT1. Analysis of PeCa tumours 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 PeCa 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, 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.
Conclusion: 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.
Written by:
Feber A, Arya M, de Winter P, Saqib M, Nigam R, Malone PR, Tan WS, Rodney S, Lechner M, Freeman A, Jameson C, Muneer A, Beck S, Kelly JD. Are you the author?
Cancer Insitute, University College London; Barts Cancer Institute, Queen Mary University of London; Division of Surgery & Interventional Science, University College London Hospital; Urology, The Royal Surrey County Hospital; Urology, The Royal Berkshire NHS Foundation Trust; Department of Virology, University College London; Histopathology, University College London; Histopathology, University College London Hospitals; Department of Urology, University College London Hospital; University College London; UCL Medical School, University College London.
Reference: Clin Cancer Res. 2014 Dec 23. pii: clincanres.1656.2014.
doi: 10.1158/1078-0432.CCR-14-1656
PubMed Abstract
PMID: 25538261