PD46-03 GENOMIC HALLMARKS OF RENAL MEDULLARY CARCINOMA

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology I1 Apr 2018PD46-03 GENOMIC HALLMARKS OF RENAL MEDULLARY CARCINOMA Jesse M. Fox, Denise Young, Yingjie Song, Heng Cheng Hu, Anthony Soltis, Matthew Wilkerson, Clifton L. Dalgard, Inger L. Rosner, Shiv Srivastava, Isabell A. Sesterhenn, and Shyh-Han Tan Jesse M. FoxJesse M. Fox More articles by this author , Denise YoungDenise Young More articles by this author , Yingjie SongYingjie Song More articles by this author , Heng Cheng HuHeng Cheng Hu More articles by this author , Anthony SoltisAnthony Soltis More articles by this author , Matthew WilkersonMatthew Wilkerson More articles by this author , Clifton L. DalgardClifton L. Dalgard More articles by this author , Inger L. RosnerInger L. Rosner More articles by this author , Shiv SrivastavaShiv Srivastava More articles by this author , Isabell A. SesterhennIsabell A. Sesterhenn More articles by this author , and Shyh-Han TanShyh-Han Tan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2151AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Renal medullary carcinoma (RMC) is a rare renal neoplasm accounting for less than 1% of all renal cell carcinomas. RMC, which frequently occurs in young African Americans with sickle cell trait, is an aggressive and lethal cancer with a median overall survival of about 13 months. Recent studies identified the biallelic loss of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex, as a characteristic feature of RMC tumors. Other reports suggest that the presence of vinculin-anaplastic lymphoma kinase (VCL-ALK) fusion without SMARCB1 loss may represent an RMC variant. We hypothesize that in addition to these alterations, novel driver mutations are present and may become potential targets for treatment. To test this hypothesis, we carried out whole exome sequencing of RMC tumor specimens. METHODS Formalin fixed paraffin embedded (FFPE) RMC tumor and adjacent normal tissue specimens of 21 African American patients with sickle cell trait were obtained from the Joint Pathology Center. RNA and DNA were isolated using the Qiagen FFPE All Prep kit. Quantity and integrity of DNA samples were evaluated by Qubit fluorometer and Advanced Analytical Fragment Analyzer, respectively. Whole exome DNA libraries were prepared from sample using the Illumina TruSeq Exome kit. Paired end sequencing (2x75) were performed on the Illumina HiSeq3000 instrument. In parallel with genomic evaluations, known RMC associated molecular alterations, including SMARCB1, VHL, HIF2A, AURKA, and EZH2, were analyzed by immunohistochemistry (IHC). RESULTS Somatic copy number alterations were estimated from the whole exome sequencing of seven tumor normal pairs. Recurrent amplifications of chromosome 7 and 8 and deletions on chromosome 15 were identified. Analysis of somatic sequence mutations detected recurrent non-silent mutations on NF2 and RBM47, and a canonical hotspot mutation (R132C) in IDH1. IHC results show the loss of SMARCB1 expression in all 21 cases assayed. Furthermore, the up-regulation of EZH2 and AURKA, genes normally repressed by SMARCB1, were detected in 3 of 21 and 11 of 21 cases, respectively. Focal HIF2A staining was detected in 7 of 21 tumor cases. CONCLUSIONS The discovery of recurrent somatic sequence mutations, gene amplifications and deletions reveals potential novel oncogenic drivers of RMC. Further validation of these genomic alterations may offer additional insight into the etiology of RMC and new options to manage the disease. The inactivation of SMARCB1 protein expression and upregulation of EZH2 and AURKA supports the evaluation of epigenetic modulating agents for treatment of RMC. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e891-e892 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Jesse M. Fox More articles by this author Denise Young More articles by this author Yingjie Song More articles by this author Heng Cheng Hu More articles by this author Anthony Soltis More articles by this author Matthew Wilkerson More articles by this author Clifton L. Dalgard More articles by this author Inger L. Rosner More articles by this author Shiv Srivastava More articles by this author Isabell A. Sesterhenn More articles by this author Shyh-Han Tan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...