Collecting duct carcinoma of the kidney is associated with CDKN2A deletion and SLC family gene up-regulation

// Jianmin Wang 1,* , Antonios Papanicolau-Sengos 2,* , Sreenivasulu Chintala 3,10,* , Lei Wei 1 , Biao Liu 1 , Qiang Hu 1 , Kiersten Marie Miles 2 , Jeffrey M. Conroy 2 , Sean T. Glenn 4 , Manuela Costantini 5,8,9 , Cristina Magi-Galluzzi 6 , Sabina Signoretti 7 , Toni Choueiri 7 , Michele Gallucci 5 , Steno Sentinelli 5 , Vito M. Fazio 8 , Maria Luana Poeta 9 , Song Liu 1 , Carl Morrison 2 and Roberto Pili 3,10 1 Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA 2 Department of Pathology and Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA 3 Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA 4 Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA 5 Department of Urology, Regina Elena National Cancer Institute of Rome, Rome, Italy 6 Department of Pathology, Cleveland Clinic, Cleveland, OH, USA 7 Department of Pathology and Kidney Cancer Program, Dana Farber, Boston, MA, USA 8 Laboratory of Genetic and Clinical Pathology, University Campus BioMedico of Rome, Rome, Italy 9 Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy 10 Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA * These authors have contributed equally to this work Correspondence to: Roberto Pili, email: // Keywords : collecting duct carcinoma, CDKN2A, solute carrier family genes Received : December 04, 2015 Accepted : April 16, 2016 Published : April 28, 2016 Abstract The genetic landscape and molecular features of collecting duct carcinoma (CDC) of the kidney remain largely unknown. Herein, we performed whole exome sequencing (WES) and transcriptome sequencing (RNASeq) on 7 CDC samples (CDC1 -7). Among the 7 samples, 4 samples with matched non-tumor tissue were used for copy number analysis by SNP array data. No recurrent somatic SNVs were observed except for MLL , which was found to be mutated (p.V297I and p.F407C) in 2 samples. We identified somatic SNVs in 14 other cancer census genes including: ATM, CREBBP, PRDM1, CBFB, FBXW7, IKZF1, KDR, KRAS, NACA, NF2, NUP98, SS18, TP53 , and ZNF521 . SNP array data identified a CDKN2A homozygous deletion in 3 samples and SNV analysis showed a non-sense mutation of the CDKN2A gene with unknown somatic status. To estimate the recurrent rate of CDKN2A abnormalities, we performed FISH screening of additional samples and confirmed the frequent loss (62.5%) of CDKN2A expression. Since cisplatin based therapy is the common treatment option for CDC, we investigated the expression of solute carrier (SLC) family transporters and found 45% alteration. In addition, SLC7A11 (cystine transporter, xCT), a cisplatin resistance associated gene, was found to be overexpressed in 4 out of 5 (80%) cases of CDC tumors tested, as compared to matched non-tumor tissue. In summary, our study provides a comprehensive genomic analysis of CDC and identifies potential pathways suitable for targeted therapies.