CSN1 Somatic Mutations in Penile Squamous Cell Carcinoma.
Other than an association with HPV infection, little is known about the genetic alterations determining the development of penile cancer. Although penile cancer 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 penile cancer. WES was performed on penile cancer 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 were also integrated with DNA methylation and copy-number information from the same patients. We identified an HPV-associated APOBEC mutation signature and an NpCpG signature in HPV-negative disease. We also identified recurrent mutations in the novel penile cancer tumor suppressor genes CSN1(GPS1) and FAT1 Expression of CSN1 mutants in cells resulted in colocalization 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 penile cancer, highlighting the complex landscape of alterations in this malignancy. Cancer Res; 76(16); 4720-7. ©2016 AACR.
UCL Cancer Institute, University College London, London, United Kingdom.
Andrew
A
Feber
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Daniel C
DC
Worth
UCL Cancer Institute, University College London, London, United Kingdom.
Ankur
A
Chakravarthy
Division of Surgery and Interventional Science, UCL Medical School, University College London, London, United Kingdom.
Patricia
P
de Winter
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Kunal
K
Shah
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.|Department of Urology, University College Hospital, London, United Kingdom.
Manit
M
Arya
Department of Urology, University College Hospital, London, United Kingdom.
Muhammad
M
Saqib
Department of Urology, The Royal Surrey County Hospital, Surrey, United Kingdom.
Raj
R
Nigam
Department of Urology, The Royal Berkshire NHS Foundation Trust, Reading, United Kingdom.
Peter R
PR
Malone
Division of Surgery and Interventional Science, UCL Medical School, University College London, London, United Kingdom.
Wei Shen
WS
Tan
Division of Surgery and Interventional Science, UCL Medical School, University College London, London, United Kingdom.
Simon
S
Rodney
Department of Histopathology, University College London Hospital, London, United Kingdom.
Alex
A
Freeman
Department of Histopathology, University College London Hospital, London, United Kingdom.
Charles
C
Jameson
UCL Cancer Institute, University College London, London, United Kingdom.
Gareth A
GA
Wilson
Experimental Cancer Medicine Centre, Barts Cancer Institute, Barts Health and the Royal Free NHS Trust, Queen Mary University of London, London, United Kingdom.
Tom
T
Powles
UCL Cancer Institute, University College London, London, United Kingdom.
Stephan
S
Beck
UCL Cancer Institute, University College London, London, United Kingdom.
Tim
T
Fenton
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Tyson V
TV
Sharp
Department of Urology, University College Hospital, London, United Kingdom.|NIHR Biomedical Research Centre, University College London Hospitals, London, United Kingdom.
Asif
A
Muneer
Division of Surgery and Interventional Science, UCL Medical School, University College London, London, United Kingdom.
John D
JD
Kelly
D000075686:COP9 Signalosome Complex; D015820:Cadherins / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005455:Fluorescent Antibody Technique; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation; D010412:Penile Neoplasms / Q000235:genetics*; D016133:Polymerase Chain Reaction
D015820:Cadherins; C502403:FAT1 protein, human; C103315:GPS1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D000075686:COP9 Signalosome Complex