Molecular profiling of primary renal diffuse large B-cell lymphoma unravels a proclivity for immune-privileged tropism

Primary renal manifestations of diffuse large B-cell lymphoma (prDLBCL) represent an exceptionally rare variant of the most common type of non-Hodgkin lymphoma (NHL).Insights into prDLBCL pathogenesis have been limited to small case series and methodologically limited approaches.To address this gap, we conducted the largest comprehensive molecular study of prDLBCL to date, analyzing 30 cases using whole exome sequencing, RNA sequencing, and somatic copy number alteration profiling.The mechanisms driving lymphomagenesis within an organ lacking an intrinsic lymphatic niche and its proclivity for dissemination to immune-privileged sites, including testes and the central nervous system, remain poorly understood.Our findings reveal significant molecular similarities to primary large B-cell lymphomas of immune-privileged sites (IP-LBCL), including a high frequency of immune-escape mechanisms, particularly through deleterious MHC class I and II aberrations and loss of CDKN2A.Despite significant mutational heterogeneity with a broad distribution among molecular clusters, transcriptional deregulation of interferon signaling and MYC target pathways emerged as key hallmarks of prDLBCL pathogenesis.Our comprehensive analysis of prDLBCL biology significantly advances the molecular understanding of this rare variant.These insights not only highlight shared pathogenetic pathways with IP-LBCL but also uncover unique features of prDLBCL, offering potential biomarkers for diagnostic refinement and therapeutic targeting.These findings have profound implications for the future development of diagnostic algorithms and risk-adapted therapeutic approaches, potentially improving the clinical management of this rare and challenging lymphoma subtype.