Andrew L Hong, Yuen-Yi Tseng, Jeremiah A Wala, Won-Jun Kim, Bryan D Kynnap, Mihir B Doshi, Guillaume Kugener, Gabriel J Sandoval, Thomas P Howard, Ji Li, Xiaoping Yang, Michelle Tillgren, Mahmhoud Ghandi, Abeer Sayeed, Rebecca Deasy, Abigail Ward, Brian McSteen, Katherine M Labella, Paula Keskula, Adam Tracy, Cora Connor, Catherine M Clinton, Alanna J Church, Brian D Crompton, Katherine A Janeway, Barbara Van Hare, David Sandak, Ole Gjoerup, Pratiti Bandopadhayay, Paul A Clemons, Stuart L Schreiber, David E Root, Prafulla C Gokhale, Susan N Chi, Elizabeth A Mullen, Charles Wm Roberts, Cigall Kadoch, Rameen Beroukhim, Keith L Ligon, Jesse S Boehm, William C Hahn
Renal medullary carcinoma (RMC) is a rare and deadly kidney cancer in patients of African descent with sickle cell trait. We have developed faithful patient-derived RMC models and using whole-genome sequencing, we identified loss-of-function intronic fusion events in one SMARCB1 allele with concurrent loss of the other allele. Biochemical and functional characterization of these models revealed that RMC requires the loss of SMARCB1 for survival. Through integration of RNAi and CRISPR-Cas9 loss-of-function genetic screens and a small-molecule screen, we found that the ubiquitin-proteasome system (UPS) was essential in RMC...
March 12, 2019: ELife