Defining the origin, evolution, and immune composition of SDH-deficient renal cell carcinoma
Joana B. Neves,
Kirsty Roberts,
Janani Sivakumaran Nguyen,
Soha El Sheikh,
My-Anh Tran-Dang,
Catherine Horsfield,
Faiz Mumtaz,
Peter Campbell,
Hans Stauss,
Maxine G.B. Tran,
Thomas Mitchell
Affiliations
Joana B. Neves
UCL Division of Surgery and Interventional Science, Royal Free Hospital, London, UK; Specialist Centre for Kidney Cancer, Royal Free Hospital, London, UK; UCL Institute of Immunity & Transplantation, The Pears Building, Pond Street, London, UK
Kirsty Roberts
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
Janani Sivakumaran Nguyen
UCL Institute of Immunity & Transplantation, The Pears Building, Pond Street, London, UK
Soha El Sheikh
Department of Histopathology, Royal Free Hospital, London, UK
My-Anh Tran-Dang
Department of Histopathology, Royal Free Hospital, London, UK
Catherine Horsfield
Guy’s & St Thomas’ National Health Service Trust, Westminster Bridge Road, London, UK
Faiz Mumtaz
UCL Division of Surgery and Interventional Science, Royal Free Hospital, London, UK; Specialist Centre for Kidney Cancer, Royal Free Hospital, London, UK
Peter Campbell
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
Hans Stauss
UCL Institute of Immunity & Transplantation, The Pears Building, Pond Street, London, UK
Maxine G.B. Tran
UCL Division of Surgery and Interventional Science, Royal Free Hospital, London, UK; Specialist Centre for Kidney Cancer, Royal Free Hospital, London, UK; UCL Institute of Immunity & Transplantation, The Pears Building, Pond Street, London, UK
Thomas Mitchell
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK; Department of Surgery, University of Cambridge, Cambridge, UK; Corresponding author
Summary: Succinate 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.
