The role of circulating gene variants in penile carcinoma

Penile squamous cell carcinoma (PSCC) is highly prevalent in low- and middle-income countries and is associated with significant rates of morbidity and mortality. Lymph node involvement is the most critical predictor of survival, making management approaches essential for improving oncological outcomes. Despite advancements in minimally invasive staging techniques, no accurate method for detecting lymph node involvement has yet been developed. While resecting positive lymph nodes is crucial for patient survival, lymph node dissection can lead to considerable morbidity. This study aims to identify circulating gene variants that could assist in detecting positive lymph nodes in patients treated for PSCC. We employed liquid biopsy and next-generation sequencing to identify circulating variants in 42 genes associated with tumor development and progression. This analysis included 21 men who underwent total or partial penectomy and inguinal and/or pelvic lymphadenectomy. We found that patients with lymph node metastases exhibited a significant higher number of circulating gene variants. An unexpected finding was the presence of uncommon pathogenic variants in the NF1 gene in the majority of patients. In conclusion, the detection of a higher number of circulating variants may help in selecting patients for inguinal and/or pelvic lymphadenectomy, ultimately improving cure rates and reducing morbidity. Furthermore, the high prevalence of pathogenic variants in NF1 gene suggests that this variant have a crucial role in the carcinogenesis processes and may serve as biomarkers for diagnosis and/or predisposition to PSCC.