Mutational landscape of penile squamous cell carcinoma in a Chinese population

Abstract

Penile squamous cell carcinoma (PSCC) is a malignancy that affects the skin and tissues of the penis, but the knowledge of pathogenesis and carcinogenesis is limited. Here, we characterize the PSCC genomic landscape using whole‐exome sequencing. Of the 30 paired blood and tumor samples, we identified recurrent mutations in 11 genes; confirmed previous findings for FAT1 (4/30), HRAS (4/30), NOTCH1 (4/30), TP53 (3/30) and PIK3CA (3/30); and revealed novel candidate driver genes [CASP8 (4/30), SLITRK2 (3/30), FLG (3/30) and TRRAP (3/30)]. Our in vitro experiments suggested CASP8 was involved in mediating TRAIL‐induced apoptosis of penile cancer cell lines. We also observed the frequently altered pathways for potential therapeutic implications: alterations in the Notch (30% of sample altered), RTK–RAS (26.7% altered) and Hippo (23.3% altered) pathways accounted for over 50% of tumors. The frequently altered genes (>10%) in these pathways were proved to be expressed in penile tumors by immunohistochemistry assay. These findings provide new insight into the mutational and pathway landscapes of PSCC and suggest potential novel therapeutic opportunities for this malignancy.

Copy Number Analysis Reveal Genetic Risks of Penile Cancer

“…The present study was based on the previous study in the samples and another five samples was added to the present study but not done HPV detection. SNPs have been reported in the previous study ( 6 ), so we’re not going to repeat it here.…”

“…The genetic and molecular basis of PeC is still poorly understood ( 5 ), and further understanding of these aspects is important to improve our ability to diagnose, treat and prevent PeC. In our previous study ( 6 ), we characterized the PSCC genomic landscape using whole-exome sequencing. Of the 30 paired blood and tumor samples, recurrent mutations were identified in 11 genes; we also observed the frequently altered pathways for potential.…”

“…Several studies have detected somatic changes that arise in (3)(4)(5), but few of them were based on whole-exome sequencing (5). Our previous study has performed a wholeexome sequencing analysis of PeC, and identified recurrent mutations in 11 genes (6).…”

TERT Promoter Mutations in Penile Squamous Cell Carcinoma: High Frequency in Non-HPV-related Type and Association With Favorable Clinicopathologic Features

“…TERT-p mutations were detected at a high frequency (48.6%) in penile SCC, which, to our knowledge, are the most frequent mutations in penile SCC described to date [34]. Indeed, the majority of recurrent mutations reported in penile SCC are of low incidence (less than 10%) [34,35]. Notably, of the 18 cases with TERT-p mutations, 14 were c.-146 C > T and three were c.-124 C > T, which are known as mutation hotspots that have been reported as the most common recurrent mutations in various organs and tend to be mutually exclusive, with two exceptions in which both mutations were identi ed in two cases of breast cancer [24].…”

“…There have been only a few studies conducted on genetic alterations in penile SCC, including data obtained through whole-exome sequencing [34,35]. In general, the detection rates are low in all cases (detection rates of 3-9%), the main mutated genes identi ed in penile SCC include KRAS, HRAS, NRAS, and PIK3CA, which are involved in the MAPK pathway [4,34,35,42]. BRAF mutation was also described in 2 out of 65 penile SCCs examined in one study, but the mutational status of TERT-p was not investigated in that cohort [34].…”