A comprehensive molecular analysis of 161 papillary renal cell carcinomas (PRCCs) revealed distinct genetic and molecular differences between Type 1 and Type 2 PRCCs. Type 1 PRCCs were characterized by MET mutations, while Type 2 PRCCs showed CDKN2A silencing, SETD2 mutations, TFE3 fusions, and activation of the NRF2-ARE pathway. Type 2 PRCCs were further divided into subtypes based on molecular features, including a CpG island methylator phenotype (CIMP) associated with poor prognosis. The study identified key genetic alterations, such as MET mutations in Type 1 and CDKN2A loss in Type 2, which are linked to different clinical outcomes. Additionally, TFE3/TFEB fusions were found in some Type 2 tumors, highlighting their significance in this subtype. The findings suggest that PRCCs are heterogeneous, with distinct molecular subtypes that may influence treatment strategies. The study underscores the importance of molecular profiling in guiding clinical decisions and developing targeted therapies for PRCC patients.A comprehensive molecular analysis of 161 papillary renal cell carcinomas (PRCCs) revealed distinct genetic and molecular differences between Type 1 and Type 2 PRCCs. Type 1 PRCCs were characterized by MET mutations, while Type 2 PRCCs showed CDKN2A silencing, SETD2 mutations, TFE3 fusions, and activation of the NRF2-ARE pathway. Type 2 PRCCs were further divided into subtypes based on molecular features, including a CpG island methylator phenotype (CIMP) associated with poor prognosis. The study identified key genetic alterations, such as MET mutations in Type 1 and CDKN2A loss in Type 2, which are linked to different clinical outcomes. Additionally, TFE3/TFEB fusions were found in some Type 2 tumors, highlighting their significance in this subtype. The findings suggest that PRCCs are heterogeneous, with distinct molecular subtypes that may influence treatment strategies. The study underscores the importance of molecular profiling in guiding clinical decisions and developing targeted therapies for PRCC patients.