title: SQSTM1 is a pathogenic target of 5q copy number gains in kidney cancer.
abstract: Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer and is often linked to loss of chromosome 3p, which harbors the VHL tumor suppressor gene, loss of chromosome 14q, which includes HIF1A, and gain of chromosome 5q. The relevant target(s) on chromosome 5q is not known. Here, we show that 5q amplification leads to overexpression of the SQSTM1 oncogene in ccRCC lines and tumors. Overexpression of SQSTM1 in ccRCC lines promoted resistance to redox stress and increased soft agar growth, while downregulation of SQSTM1 decreased resistance to redox stress, impaired cellular fitness, and decreased tumor formation. Therefore, the selection pressure to amplify 5q in ccRCC is driven, at least partly, by SQSTM1.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Lianjie
authors: L
authors: Li
authors: Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Chuan
authors: C
authors: Shen
authors: Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Eijiro
authors: E
authors: Nakamura
authors: Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Kiyohiro
authors: K
authors: Ando
authors: Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Sabina
authors: S
authors: Signoretti
authors: Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Rameen
authors: R
authors: Beroukhim
authors: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Glenn S
authors: GS
authors: Cowley
authors: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Patrick
authors: P
authors: Lizotte
authors: Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors: Ella
authors: E
authors: Liberzon
authors: Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Steven
authors: S
authors: Bair
authors: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: David E
authors: DE
authors: Root
authors: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Pablo
authors: P
authors: Tamayo
authors: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Aviad
authors: A
authors: Tsherniak
authors: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Su-Chun
authors: SC
authors: Cheng
authors: Department of Cancer Biology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Barbara
authors: B
authors: Tabak
authors: Department of Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 16605, USA.
authors: Anders
authors: A
authors: Jacobsen
authors: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 16605, USA.
authors: A Ari
authors: AA
authors: Hakimi
authors: Department of Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 16605, USA.
authors: Nikolaus
authors: N
authors: Schultz
authors: Department of Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 16605, USA.
authors: Giovanni
authors: G
authors: Ciriello
authors: Department of Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 16605, USA.
authors: Chris
authors: C
authors: Sander
authors: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 16605, USA; Department of Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 16605, USA.
authors: James J
authors: JJ
authors: Hsieh
authors: Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: william_kaelin@dfci.harvard.edu.
authors: William G
authors: WG
authors: Kaelin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D045744:Cell Line, Tumor; D002895:Chromosomes, Human, Pair 5; D018628:Gene Dosage; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D051267:NF-E2-Related Factor 2 / Q000032:analysis / Q000502:physiology; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein