Comparative analysis of the roles of PBRM1 and SETD2 genes in the pathogenesis and progression of renal cell carcinoma: An analytical review.

Clear cell renal cell carcinoma (ccRCC) is characterized by frequent mutations in chromatin-modifying genes, notably PBRM1 and SETD2, which play critical roles in tumorigenesis and disease progression. These mutations affect chromatin remodeling and histone methylation, influencing cellular functions such as tumor suppression, genomic integrity, and cell cycleregulation. Despite their prevalence, the distinct biological impacts and clinical implications of PBRM1 and SETD2 mutations remain incompletely understood. This review aims to elucidate the functional similarities and differences between PBRM1 and SETD2 mutations in ccRCC, investigate their roles in tumor progression and metastasis, and assess the potential clinical and therapeutic implications of these genetic alterations in the context of precision oncology. A comprehensive literature review was conducted, analyzing genomic, transcriptomic, and clinical data from ccRCC cohorts. Functional studies of PBRM1 and SETD2 mutations were examined alongside gene set enrichment analyses (GSEA), histopathologic observations, and molecular profiling of primary and metastatic tumor sites. Recent advances in therapeutic strategies targeting these mutations were also reviewed. PBRM1 mutations occur early in ccRCC development, altering chromatin accessibility and acting as tumor co-initiators, while SETD2 mutations arise later, exacerbating genomic instability and promoting metastasis. Both genes share tumor suppressor functions but differ in their genetic interactions and pathways. Co-mutation of PBRM1 and SETD2 correlates with increased tumor aggressiveness, poor prognosis, and higher metastatic potential. Emerging therapeutic approaches, including targeted molecular therapies and immunotherapies, show promise in addressing these mutation-driven pathways. PBRM1 and SETD2 mutations critically influence the molecular pathogenesis and clinical outcomes of ccRCC. Understanding their distinct and cooperative roles can enhance molecular profiling and guide personalized treatment strategies. Further research is warranted to develop targeted therapies that exploit the vulnerabilities associated with these chromatin-modifying gene mutations, ultimately improving prognosis and therapeutic response in ccRCC patients.