Penile squamous cell carcinoma (PSCC) can be classified into human papilloma virus-positive (HPV+) and HPV-independent (HPV–). HPV+ tumours have higher rates of poorly differentiated disease than HPV– tumours. However, a lower cancer-specific mortality (CSM) has been reported in patients with HPV+ versus HPV– disease. This evidence might be partially explained by a disproportionate occurrence of loss-of-function mutations of TP53 (TP53LOF) in patients with HPV– versus HPV+ disease.

In a study published in European Urology, a PSCC single-cell RNA sequencing (scRNA-seq) atlas was established to identify molecular characteristics that might explain prognostic differences observed between patients with HPV+ and HPV– tumours. scRNA-seq and T cell receptor sequencing were carried out in 16 fresh tumour samples from patients with treatment-naive primary PSCC and 6 non-malignant inner prepuce samples. A total of four groups were defined based on HPV and TP53 status: normal (n = 6), HPV+TP53 wild-type (WT; n = 6), HPV–TP53WT (n = 6) and TP53LOF (irrespective of HPV status; n = 4). Analysis of CSM of patients from an independent international cohort validated the prognostic relevance of these groups, with patients with TP53-mutated tumours having a significantly worse prognosis than patients with TP53WT tumours (P = 0.002). Results from the scRNA-seq analysis showed that TP53LOF tumours had an aggressive phenotype characterized by gene signatures of epithelial-to-mesenchymal transition, angiogenesis and immune exclusion. HPV–TP53WT tumours showed immune exhaustion, whereas HPV+TP53WT tumours showed a normal epithelial maturation and an upregulation of multiple antibody–drug conjugate targets, suggesting a potential therapeutic utility.