Genomic profiling of urological malignancies using tissue-based next generation sequencing

Advances in understanding genomic drivers of human malignancies have evolved from morphologic evaluations to in-depth DNA and RNA analyses and gene expression profiling. In urologic malignancies, these molecular diagnostics are integral to patient management, aiding pathological diagnosis, providing prognostic and predictive relevance, and identifying therapeutic options for advanced diseases. For instance, renal cell carcinoma frequently harbors alterations in VHL, PBRM1, and BAP1, influencing therapeutic responses, while urothelial carcinoma is characterized by FGFR3 mutations and TERT promoter alterations, which have implications for targeted therapy. Prostate cancer commonly involves TMPRSS2-ERG fusions and BRCA2 mutations, affecting treatment strategies, and penile squamous cell carcinoma follows distinct HPV-dependent and HPV-independent pathways, with mutations in TP53 and CDKN2A genes. These advances in molecular pathology have deepened our understanding of these complex diseases and facilitated the introduction of novel targeted therapies. While these advances promise improved diagnosis, prognosis, and treatment options, many questions remain regarding the variable patient responses within the same histologic types. Addressing these will enable optimal management strategies and the development of personalized treatments targeting specific molecular alterations to improve patient outcomes.