title: Collecting duct carcinoma of the kidney is associated with CDKN2A deletion and SLC family gene up-regulation.
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.
authors.affiliation: Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology and Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Antonios
authors.initials: A
authors.lastname: Papanicolau-Sengos
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA.
authors.forename: Sreenivasulu
authors.initials: S
authors.lastname: Chintala
authors.affiliation: Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Biao
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Pathology and Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Kiersten Marie
authors.initials: KM
authors.lastname: Miles
authors.affiliation: Department of Pathology and Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Conroy
authors.affiliation: Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Sean T
authors.initials: ST
authors.lastname: Glenn
authors.affiliation: Department of Urology, Regina Elena National Cancer Institute of Rome, Rome, Italy.|Laboratory of Genetic and Clinical Pathology, University Campus BioMedico of Rome, Rome, Italy.|Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Costantini
authors.affiliation: Department of Pathology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Magi-Galluzzi
authors.affiliation: Department of Pathology and Kidney Cancer Program, Dana Farber, Boston, MA, USA.
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.affiliation: Department of Pathology and Kidney Cancer Program, Dana Farber, Boston, MA, USA.
authors.forename: Toni
authors.initials: T
authors.lastname: Choueiri
authors.affiliation: Department of Urology, Regina Elena National Cancer Institute of Rome, Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Gallucci
authors.affiliation: Department of Urology, Regina Elena National Cancer Institute of Rome, Rome, Italy.
authors.forename: Steno
authors.initials: S
authors.lastname: Sentinelli
authors.affiliation: Laboratory of Genetic and Clinical Pathology, University Campus BioMedico of Rome, Rome, Italy.
authors.forename: Vito M
authors.initials: VM
authors.lastname: Fazio
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: Maria Luana
authors.initials: ML
authors.lastname: Poeta
authors.affiliation: Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Pathology and Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Morrison
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D017353:Gene Deletion; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006720:Homozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017423:Sequence Analysis, RNA; D015854:Up-Regulation; D000073359:Exome Sequencing
chemical_list: D027182:Amino Acid Transport System y+; C497422:KMT2A protein, human; C118895:SLC7A11 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase
keywords: CDKN2A; collecting duct carcinoma; solute carrier family genes