Identification of somatic gene mutations in penile squamous cell carcinoma

Abstract

There is a lack of studies on somatic gene mutations and cell signaling driving penile carcinogenesis. Our objective was to analyze somatic mutations in genes downstream of EGFR in penile squamous cell carcinomas, especially the mTOR and RAS/MAPK pathways. We retrospectively analyzed somatic mutations in 10 in situ and 65 invasive penile squamous cell carcinomas by using Sequenom's Mass Spectrometry iPlex Technology and Oncocarta v1.0 Panel. The DNA was extracted from FFPE blocks and we identified somatic missense mutations in three in situ tumors and in 19 invasive tumors, mostly in PIK3CA, KRAS, HRAS, NRAS, and PDGFA genes. Somatic mutations in the PIK3CA gene or RAS family genes were neither associated with tumor grade, stage or outcome, and were equally often identified in hrHPV positive and in hrHPV negative tumors that showed no p53 expression. Mutations in PIK3CA, KRAS, and HRAS are frequent in penile squamous cell carcinoma and likely play a role in the development of p53-negative tumors. Although the presence of these mutations does not seem to correlate with tumoral behavior or outcome, they could be biomarkers of treatment failure with anti-EGFR mAb in patients with penile squamous cell carcinoma.

Mutational landscape of penile squamous cell carcinoma in a Chinese population

“…Several studies have examined somatic mutations that arise in penile cancer, but few of them were based on hypothesis‐free approaches (such as whole‐exome sequencing). In addition, most of the participants in these studies were of European descent, and HPV infection accounted for almost 50% of cases .…”

“…In addition, most of the participants in these studies were of European descent, and HPV infection accounted for almost 50% of cases . Somatic mutations in the PIK3CA , HRAS , KRAS and STK11 genes have been previously identified in penile carcinoma samples, suggesting a potential role of the phosphatidylinositol 3‐kinase or Ras pathway . In addition, TP53 alterations, EGFR amplification and CSN1 mutation are frequent in primary penile tumor/lymph node metastases .…”

“…16 It has been reported that the vast majority of penile cancer patients had phimosis or redundant prepuce without circumcision, and thus, penile cancer risk is likely to be closely related to these conditions. 17 Several studies have examined somatic mutations that arise in penile cancer, [18][19][20][21][22] but few of them were based on hypothesisfree approaches (such as whole-exome sequencing 20 ). In addition, most of the participants in these studies were of European descent, and HPV infection accounted for almost 50% of cases.…”

“…19 Somatic mutations in the PIK3CA, HRAS, KRAS and STK11 genes have been previously identified in penile carcinoma samples, suggesting a potential role of the phosphatidylinositol 3-kinase or Ras pathway. 18,19,21 In addition, TP53 alterations, EGFR amplification and CSN1 mutation are frequent in primary penile tumor/lymph node metastases. 20,22,23 However, the etiology of penile cancer is largely unknown, and the current knowledge of the involved genetic alterations remains limited.…”

Nuclear loss and cytoplasmic expression of androgen receptor in penile carcinomas: role as a driver event and as a prognosis factor

“…Molecular alterations in PeCa have been described only recently by our group and others [19,[21][22][23][24][25][26][27][28][29][30]. Interestingly, contrary to the findings described in breast and prostate cancers, AR mRNA is down-expressed in PeCa [19].…”