title: Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling.
abstract: Collecting duct carcinoma (CDC) is a rare type of renal cell carcinoma (RCC) originating from the renal medulla. Clinical outcomes are poor, and there are no consensus guidelines to guide therapy.
  
  
  
  To determine genomic alterations (GAs) in a series of patients with locally advanced or metastatic CDC for whom genomic profiling was performed during the course of clinical care.
  
  
  
  Formalin-fixed, paraffin-embedded blocks or slides were obtained for 17 patients with CDC. DNA was extracted and comprehensive genomic profiling was performed in a laboratory certified under the Clinical Laboratory Improvement Amendments.
  
  
  
  Bayesian algorithms and local alignment algorithms were used to detect substitutions and insertions/deletions, respectively. A comparison to normal control samples was used to detect copy number alterations. Clinically relevant GAs (CRGAs) were defined as those linked to approved or investigational targeted therapies.
  
  
  
  The median age in the cohort was 53 yr (range 26-73), and 14 primary tumors and three metastatic sites assessed. A total of 36 GAs were detected in this series of patients, with an average of 2.1 GAs per case. The most common GAs were in NF2 (5/17, 29%), SETD2 (4/17, 24%), SMARCB1 (3/17, 18%), and CDKN2A (2/17, 12%). Of nine cases assessed for FH GAs, two patients had FH homozygous loss. A limitation is that targeted interrogation of genes known to be implicated in other cancers was performed, so mutations outside of these cannot be excluded.
  
  
  
  Recurrent CRGAs were detected in this series of CDC cases and suggest a possible benefit from targeted therapy. In particular, mTOR inhibitors may be of interest in patients with NF2 alterations. Alterations in FH and SMARCB1 also occurred in a mutually exclusive manner to NF2 alterations.
  
  
  
  This report provides important genomic insights into collecting duct carcinoma, a rare type of renal cell carcinoma with a very aggressive course. These insights could further rationalize the use of targeted therapies for rare tumors according to the individual genomic alterations harbored.
authors.affiliation: Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Sumanta K
authors.initials: SK
authors.lastname: Pal
authors.affiliation: Division of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Depinder
authors.initials: D
authors.lastname: Khaira
authors.affiliation: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Karam
authors.affiliation: Division of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Van Allen
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Norma A
authors.initials: NA
authors.lastname: Palma
authors.affiliation: Department of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Stein
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Squillace
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Elvin
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Juliann
authors.initials: J
authors.lastname: Chmielecki
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Department of Pathology and Laboratory Medicine, Warren Alpert School of Medicine at Brown University, Providence, RI, USA.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Yakirevich
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Douglas I
authors.initials: DI
authors.lastname: Lin
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine, Cambridge, MA, USA. Electronic address: sali@foundationmedicine.com.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Foundation Medicine, Cambridge, MA, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000556:secondary; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D056915:DNA Copy Number Variations; D000090205:DNA Methyltransferase 3A; D000073979:F-Box-WD Repeat-Containing Protein 7 / Q000235:genetics; D005260:Female; D005649:Fumarate Hydratase / Q000235:genetics; D016515:Genes, Neurofibromatosis 2; D019942:Genes, p16; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D054643:INDEL Mutation; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D007685:Kidney Tubules, Collecting; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D000071796:SMARCB1 Protein / Q000235:genetics; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D000073979:F-Box-WD Repeat-Containing Protein 7; D005649:Fumarate Hydratase; D011495:Histone-Lysine N-Methyltransferase; D019869:Phosphatidylinositol 3-Kinases; D016283:Proto-Oncogene Proteins p21(ras); D000071796:SMARCB1 Protein; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C400134:BAP1 protein, human; C000717967:DNMT3A protein, human; C513273:FBXW7 protein, human; C513266:SMARCB1 protein, human; C521636:SETD2 protein, human; C560566:phosphoinositol-3 kinase regulatory subunit 2, human; C484760:PIK3CA protein, human; C501009:HRAS protein, human; C497446:VHL protein, human
keywords: Collecting duct carcinoma; Genomic profiling; Medullary carcinoma; NF2