Penile squamous cell carcinoma (SCC) is a rare cancer that arises via two major carcinogenic routes: either associated with a transforming human papillomavirus infection (HPV) or independent of HPV, often on the background of lichenoid dermatoses. HPV-mediated carcinogenesis is well understood and associated with E6/E7 oncoproteins which disrupt cell cycle regulators p53 and Rb in host cells causing lack of proliferation control. Carcinogenesis in the absence of HPV is less well understood and believed to be associated primarily with TP53 mutations. In this genetic study of 156 invasive penile SCC from a single institution in a low-incidence country we demonstrated significantly different mutational landscapes in HPV-induced and HPV-independent SCC. Mutation at TP53 and CDKN2A were the most common and were exclusive to HPV-negative SCC. Unlike mutations in tumor suppressor genes, activating mutations in oncogenes PIK3CA and FGFR3 were unrelated to HPV status and occurred at rates similar to other cancers. Copy-number alterations (CNA) were common and complex, with frequent co-occurrences and – unlike mutations – not specific to etiology. The most common CNA included oncogene amplifications included TP63, SOX2, PIK3CA (3q), MYC, HEY, RAD21 (8q) and JAK2 (9p), and homozygous deletions affecting WRN, NRG1 (8p), BAP1, FANCD2, VHL (3p) and ARHGEF12, BCL9L, ATM (11q22/23). In contrast to mutations, CNA affecting TP53 and CDKN2A occurred at similar frequencies in HPV-induced and HPV-independent SCC. In addition, we described a dichotomy of HPV-independent carcinogenesis in two pathways: (i) SCC development via d-PeIN in chronic inflammatory dermatoses, with TP53/CDKN2A mutations and resultant p53 overexpression, and (ii) pathway in the absence of dermatoses associated with the p53 wild-type verrucous and verruciform precursors, and SCC with mutations in PIK3CA and HRAS, and amplifications affecting EGFR. A subset of patients with advanced SCC harboring targetable mutations or CNA described in this work may benefit from targeted therapy and clinical trials.
Genetic events in the progression from precancerous lesions to invasive carcinoma in penile squamous cell cancer
Ermakov, M. (Author). 2026
Student thesis: Doctoral thesis