CSN1 Somatic Mutations in Penile Squamous Cell Carcinoma
View/ Open
Published version
Embargoed until: 5555-01-01
Embargoed until: 5555-01-01
Volume
76
Pagination
4720 - 4727
Publisher
DOI
10.1158/0008-5472.CAN-15-3134
Journal
CANCER RESEARCH
Issue
ISSN
0008-5472
Metadata
Show full item recordAbstract
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 miRNAmediated 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.