Other than an association with HPV infection, little is known about the genetic alterations determining the development of penile cancer (PeCa). While PeCa is rare in the developed world, it presents a significant burden in developing countries. Here we report the findings of whole exome sequencing (WES) to determine the somatic mutational landscape of PeCa. WES was performed on PeCa and matched germline DNA from 27 patients undergoing surgical resection. Targeted resequencing of candidate genes was performed in an independent 70 patient cohort. Mutation data was also integrated with DNA methylation and copy number information from the same patients. We identified an HPV-associated APOBEC mutation signature and a NpCpG signature in HPV-negative disease. We also identified recurrent mutations in the novel PeCa tumor suppressor genes <i>CSN1(GPS1)</i> and <i>FAT1</i>. Expression of CSN1 mutants in cells resulted in co-localization with AGO2 in cytoplasmic P-bodies, ultimately leading to the loss of miRNA-mediated gene silencing which may contribute to disease etiology. Our findings represent the first comprehensive analysis of somatic alterations in PeCa, highlighting the complex landscape of alterations in this malignancy.
Cancer research. 2016 Jun 20 [Epub ahead of print]
Andrew Feber, Daniel C Worth, Ankur Chakravarthy, Patricia de Winter, Kunal Shah, Manit Arya, Muhammad Saqib, Raj Nigam, Peter R Malone, Wei Shen Tan, Simon Rodney, Alex Freeman, Charles Jameson, Gareth A Wilson, Thomas Powles, Stephan Beck, Tim Fenton, Tyson V Sharp, Asif Muneer, John D Kelly
UCL Cancer Insitute, University College London ., Centre for Molecular Oncology, Barts Cancer Institute., UCL Cancer Institute, University College London., Division of Surgery & Interventional Science, University College London Hospital., Barts Cancer Institute, Queen Mary University of London., Division of Surgery & Interventional Science, University College London Hospital., Division of Surgery & Interventional Science, University College London Hospital., Urology, The Royal Surrey County Hospital., Urology, The Royal Berkshire NHS Foundation Trust., Division of Surgery & Interventional Science, University College London Hospital., Division of Surgery & Interventional Science, University College London., Histopathology, University College London., Histopathology, University College London Hospitals., The Francis Crick Institute., Experimental Cancer Medicine Centre, Queen Mary University of London., UCL Cancer Institute, University College London., Department of Virology, University College London., Centre for Molecular Oncology, Barts Cancer Institute., Urology, University College Hospital., Division of Surgery and Interventional Science, University College London.