title: Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets.
abstract: Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell renal cell carcinomas that have no standard therapy. The oncogenic drivers in these tumours are unknown. Here we perform a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, single-nucleotide polymorphism array, fluorescence in situ hybridization, immunohistochemistry and cell-based assays. We identify recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%) and MTOR (8%). Integrated analysis reveals a subset of 26% uRCC characterized by NF2 loss, dysregulated Hippo-YAP pathway and worse survival, whereas 21% uRCC with mutations of MTOR, TSC1, TSC2 or PTEN and hyperactive mTORC1 signalling are associated with better clinical outcome. FH deficiency (6%), chromatin/DNA damage regulator mutations (21%) and ALK translocation (2%) distinguish additional cases. Altogether, this study reveals distinct molecular subsets for 76% of our uRCC cohort, which could have diagnostic and therapeutic implications.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Ying-Bei
authors.identifier: 0000-0001-5207-3648
authors.initials: YB
authors.lastname: Chen
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Jianing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Computational Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Anders Jacobsen
authors.initials: AJ
authors.lastname: Skanderup
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Yiyu
authors.identifier: 0000-0002-5391-4936
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: A Rose
authors.initials: AR
authors.lastname: Brannon
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Helen H
authors.initials: HH
authors.lastname: Won
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Wang
authors.affiliation: Molecular Cytogenetics Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Gouri J
authors.identifier: 0000-0002-8547-1957
authors.initials: GJ
authors.lastname: Nanjangud
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Achim A
authors.initials: AA
authors.lastname: Jungbluth
authors.affiliation: Cell Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Cell Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Ojeda
authors.affiliation: Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: A Ari
authors.initials: AA
authors.lastname: Hakimi
authors.affiliation: Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Voss
authors.affiliation: Computational Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.affiliation: Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Motzer
authors.affiliation: Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Russo
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Emily H
authors.initials: EH
authors.lastname: Cheng
authors.affiliation: Cell Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Filippo G
authors.initials: FG
authors.lastname: Giancotti
authors.affiliation: Computational Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: William
authors.initials: W
authors.lastname: Lee
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Tickoo
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reuter
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Department of Medicine, Weill Cornell Medical College, 1300 York Ave, New York, New York 10065, USA.
authors.forename: James J
authors.identifier: 0000-0003-3595-0551
authors.initials: JJ
authors.lastname: Hsieh
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics*; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics*; D016518:Neurofibromatosis 2 / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics
chemical_list: C400134:BAP1 protein, human; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D043222:Ubiquitin Thiolesterase