摘要：SummarySuccinate dehydrogenase (SDH)-deficient renal cell carcinoma represents a rare subtype of hereditary kidney cancer. Clinical diagnosis can be challenging and there is little evidence to guide systemic therapeutic options. We performed genomic profiling of a cohort of tumors through the analysis of whole genomes, transcriptomes, as well as flow cytometry and immunohistochemistry in order to gain a deeper understanding of their molecular biology. We find neutral evolution after early tumor activation with a lack of secondary driver events. We show that these tumors have epithelial derivation, possibly from the macula densa, a specialized paracrine cell of the renal juxtaglomerular apparatus. They subsequently develop into immune excluded tumors. We provide transcriptomic and protein expression evidence of a highly specific tumor marker, PAPPA2. These translational findings have implications for the diagnosis and treatment for this rare tumor subtype.Graphical abstractDisplay OmittedHighlights•Whole genome sequencing indicates early initiation followed by neutral evolution•Retained transcriptional signals uncovers a putative macula densa cell of origin•Immunophenotyping demonstrates an immune-excluded microenvironment•PAPPA2 shows promising utility as a highly specific tumor markerCancer systems biology; Cancer; Genomics
