TERT Promoter Mutations in Penile Squamous Cell Carcinoma: High Frequency in Non-HPV-related Type and Association With Favorable Clinicopathologic Features

Abstract

BackgroundPenile carcinoma is a rare malignant neoplasm and its molecular pathogenetic mechanism is largely unknown. Telomerase reverse transcriptase (TERT) promoter mutations have been detected in several types of human malignancies, including malignant melanoma, non-melanoma skin cancer, thyroid carcinoma, glioma, and bladder carcinoma. However, TERT-p mutation in penile squamous cell carcinoma (SCC) has not been investigated to date. The aim of this study was to investigate the presence of TERT promoter mutations in penile squamous cell carcinomas and their associations with clinicopathologic features. MethodsSanger sequencing was performed to detect TERT promoter mutations in formalin-fixed paraffin-embedded tissue samples from 37 cases of penile SCC, 16 cases of cutaneous SCC, and 4 cases of non-neoplastic penile/skin tissue. The expression of p16 and Ki67 were investigated by immunohistochemistry. Associations of TERT promoter mutation with clinicopathological factors, immunohistochemical results, and clinical outcome were statistically analyzed. ResultsRecurrent TERT promoter mutations were identified in 18 of 37 (48.6%) penile SCCs, including all three carcinoma in situ cases. TERT promoter mutations were significantly more frequent in non-human papilloma virus (HPV)-related penile SCC types based on both histologic classification and p16INK4a immunoreactivity. Furthermore, TERT promoter mutation was associated with a low histologic grade, low mitotic count, absence of necrosis, and low Ki67/MIB-1 labelling index. Univariate Cox regression analysis and Kaplan-Meier analysis with the log-rank test indicated that TERT promoter mutation was a favorable factor for disease-free survival. ConclusionsOur study shows TERT-p mutations are the most frequent somatic mutations in penile SCC. In addition, TERT-p mutations are far more frequent in non-HPV-related penile SCC, indicating that in case of non-HPV-related penile SCC, TERT-p mutations may have a role in tumorigenesis distinct from HPV-related penile SCC.