Altered TP53, CDKN2A, ATM, EPHA7, POT1, CHEK1, GRIN2A, and EGFR Predict Shorter Survival in Penile Squamous Cell Carcinoma.

Abstract

Penile squamous cell carcinoma (pSCC) represents an uncommon malignancy characterized by stagnant mortality, psychosexual distress, and a highly variable prognosis. Currently, the WHO distinguishes between human papillomavirus (HPV) related and HPV independent pSCC. Recently, there has been an evolving line of research documenting the enrichment of HPV-independent pSCC with a high tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) expression, as well as clusters of genes associated with HPV status. In this study, we conducted comprehensive next-generation sequencing (NGS) DNA profiling of 146 pSCC samples using a panel consisting of 355 genes associated with tumors. This profiling was correlated with immunohistochemical markers and prognostic clinical data. A survival analysis of recurrent genomic events (found in ≥10 cases) was performed. TP53, CDKN2A, ATM, EPHA7, POT1, CHEK1, GRIN2A, and EGFR alterations were associated with significantly shortened overall survival (OS) in univariate and multivariate analysis. HPV positivity, diagnosed through both p16 immunohistochemistry and HPV DNA analysis, displayed no impact on survival but was associated with high grade, lymphatic invasion, PD-L1 negativity/weak expression, and low TMB. FAT1, TP53, CDKN2A, CASP8, and HRAS were more often mutated in HPV-independent pSCC. In contrast, HPV associated pSCCs were enriched by EPHA7, ATM, GRIN2A and CHEK1 mutations. PIK3CA, FAT1, FBXW7, and KMT2D mutations were associated with high TMB. NOTCH1, TP53, CDKN2A, POT1, KMT2D, ATM, CHEK1, EPHA3, and EGFR alterations were related with adverse clinical-pathological signs such as advanced stage, high tumor budding, and lymphovascular invasion. We detected 160 alterations with potential treatment implications, with 21.2% of samples showing alterations in the homologous recombination pathway. To the best of our knowledge, this study describes the largest cohort of pSCC with complex molecular-pathological, clinical, and prognostic analysis correlating with prognosis.