title: Genomic Characterization of Renal Cell Carcinoma with Sarcomatoid Dedifferentiation Pinpoints Recurrent Genomic Alterations.
abstract: The genomic features underpinning renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) are not well understood, and at present, there are no specific or effective therapies for sRCC.
  
  
  
  To identify genomic alterations in patients with sRCC.
  
  
  
  We conducted genomic profiling on paired epithelial and sarcomatoid areas of three sRCC cases. Genomic profiling was performed on another 23 sRCC patients harboring diverse epithelial components (total of 26 cases). Genomic profiling was conducted using a hybrid capture DNA next-generation sequencing assay of 236 cancer-related genes plus 19 genes frequently rearranged in cancer. Results were compared with 56 similarly sequenced cases of clear cell RCC (ccRCC) devoid of a sarcomatoid component, and with clear cell, papillary, and chromophobe renal cell carcinoma datasets from The Cancer Genome Atlas. Four additional ccRCC cases underwent whole exome sequencing.
  
  
  
  Genomic alterations in patients with sRCC and ccRCC were described, and their frequencies were compared using the Fisher exact test.
  
  
  
  Two of three patients with sRCC who underwent genomic profiling of both their epithelial and sarcomatoid components demonstrated identical mutational profiles, and a third case demonstrated commonly disrupted genes. Of the 26 sRCCs, TP53 (42.3%), VHL (34.6%), CDKN2A (26.9%), and NF2 (19.2%) were the most frequently altered genes. NF2 mutations were mutually exclusive with TP53 but not with VHL mutations. Limitations include the small sample size.
  
  
  
  We found that sRCC contains different driver mutations than ccRCC. The epithelial and sarcomatoid components of sRCC largely contain the same genomic features. On the basis of harboring either TP53 or NF2 mutations, sRCC can be divided into two groups. These findings may have implications for understanding the oncogenesis of sarcomatoid renal tumors and for defining systemic treatment options.
  
  
  
  Next-generation sequencing of tumors from patients with sarcomatoid kidney cancer reveals mutations that differ from those in nonsarcomatoid patients. These findings have implications in understanding the pathobiology of sarcomatoid kidney cancer and indicate the need for a different treatment approach in these patients.
authors.affiliation: Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre and Marie Curie (Paris VI), GRC5, ONCOTYPE-Uro, Institut Universitaire de Cancérologie, Assistance-Publique Hôpitaux de Paris, Paris, France.
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Malouf
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Sohail
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA; Department of Pathology, Albany Medical College, Albany, NY, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre and Marie Curie (Paris VI), GRC5, ONCOTYPE-Uro, Institut Universitaire de Cancérologie, Assistance-Publique Hôpitaux de Paris, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Khayat
authors.affiliation: Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Sumanta K
authors.initials: SK
authors.lastname: Pal
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kanishka
authors.initials: K
authors.lastname: Sircar
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Pheroze
authors.initials: P
authors.lastname: Tamboli
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Jonasch
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Nizar M
authors.initials: NM
authors.lastname: Tannir
authors.affiliation: Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Wood
authors.affiliation: Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: JAKaram@mdanderson.org.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Karam
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics*; D005260:Female; D016515:Genes, Neurofibromatosis 2 / Q000502:physiology*; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D017422:Sequence Analysis, DNA; D013223:Statistics as Topic; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
keywords: Genomic; Profiling; Renal cell carcinoma; Sarcomatoid; Sequencing; p53