Different Mutational Landscapes in Human Papillomavirus–Induced and Human Papillomavirus–Independent Invasive Penile Squamous Cell Cancers

Abstract

Penile squamous cell carcinoma (SCC) are rare cancers that arise after transforming human papillomavirus (HPV) infections or independent of HPV in the background of chronic dermatoses. Limited knowledge about genetic alterations driving penile carcinogenesis comes from studies of mainly small cohorts of typically mixed etiology. In this comparative genetic study of HPV-induced and HPV-independent invasive penile SCC of 157 patients from a single institution in a low-incidence country, hot spots of 50 cancer-relevant genes were analyzed with targeted next-generation sequencing. 79/157 SCC were classified as HPV-induced, 78/157 SCC arose independent of HPV. Only 29/79 (37%) of HPV-induced penile SCC, but 69/79 (88%) of HPV-independent SCC carried somatic gene mutations. PIK3CA, FGFR3, and FBXW7 mutations occurred in both groups in similar numbers as seen in other human cancers. In contrast, mutations in TP53 (44/79; 59%), CDKN2A (35/79; 43%), and HRAS (12/79; 15%) occurred with one exception exclusively in HPV-independent SCC with a frequent co-occurrence of TP53 and CDKN2A mutations (27/78; 36%). Mutations in multiple genes occurred in 10/79 (13%) HPV-induced SCC versus 48/78 (62%) HPV-independent SCC (Chi square; p< 0.001). More than one mutation per gene (multi hits) was characteristic for HPV-independent SCC in 14/78 (18%) compared to only 3/79 (4%) HPV-induced SCC (Chi square; p< 0.001). The total number of mutations in HPV-induced penile SCC (48 mutations) was significantly lower than in HPV-independent (145 mutations; Welsh test; p<0.001). The presence of somatic driver gene mutations did not correlate with the age of patients, histology, or tumor stage of the primary SCC in either etiologic group, suggesting that acquisition of driver gene mutations is an early event after invasion. This large cohort analysis identified characteristic differences in mutational landscapes for the two etiologies. While genetic mutations in tumor suppressor genes drive HPV-independent penile carcinogenesis, oncogenic action of E6 and E7 substitute for mutations in HPV-induced SCC. A subgroup of patients with advanced SCC may be candidates for targeted therapy and clinical trials, although the majority of advanced penile SCC remain a therapeutic challenge.

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