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The Genetic Basis of Hepatosplenic T-cell Lymphoma.

  • McKinney M Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
  • Moffitt AB Duke Center for Genomics and Computational Biology, Duke University, Durham, North Carolina.
  • Gaulard P Hôpital Henri Mondor, Department of Pathology, AP-HP, Créteil, France, INSERM U955, Créteil, France, and University Paris-Est, Créteil, France.
  • Travert M Hôpital Henri Mondor, Department of Pathology, AP-HP, Créteil, France, INSERM U955, Créteil, France, and University Paris-Est, Créteil, France.
  • De Leval L Pathology Institute, CHUV Lausanne, Switzerland.
  • Nicolae A Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  • Raffeld M Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  • Jaffe ES Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  • Pittaluga S Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  • Xi L Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  • Heavican T University of Nebraska, Omaha, Nebraska.
  • Iqbal J University of Nebraska, Omaha, Nebraska.
  • Belhadj K Hôpital Henri Mondor, Department of Pathology, AP-HP, Créteil, France, INSERM U955, Créteil, France, and University Paris-Est, Créteil, France.
  • Delfau-Larue MH Hôpital Henri Mondor, Department of Pathology, AP-HP, Créteil, France, INSERM U955, Créteil, France, and University Paris-Est, Créteil, France.
  • Fataccioli V Hôpital Henri Mondor, Department of Pathology, AP-HP, Créteil, France, INSERM U955, Créteil, France, and University Paris-Est, Créteil, France.
  • Czader MB Indiana University, Indianapolis, Indiana.
  • Lossos IS University of Miami, Miami, Florida.
  • Chapman-Fredricks JR University of Miami, Miami, Florida.
  • Richards KL University of North Carolina, Chapel Hill, North Carolina.
  • Fedoriw Y University of North Carolina, Chapel Hill, North Carolina.
  • Ondrejka SL Cleveland Clinic, Cleveland, Ohio.
  • Hsi ED Cleveland Clinic, Cleveland, Ohio.
  • Low L City of Hope Medical Center, Duarte, California.
  • Weisenburger D City of Hope Medical Center, Duarte, California.
  • Chan WC City of Hope Medical Center, Duarte, California.
  • Mehta-Shah N Memorial Sloan Kettering Cancer Center, New York, New York.
  • Horwitz S Memorial Sloan Kettering Cancer Center, New York, New York.
  • Bernal-Mizrachi L Emory University, Atlanta, Georgia.
  • Flowers CR Emory University, Atlanta, Georgia.
  • Beaven AW Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
  • Parihar M Tata Medical Center, Kolkata, India.
  • Baseggio L Centre Lyon-Sud, Pierre-Bénite, France.
  • Parrens M Hôpital Pessac, Bordeaux, France.
  • Moreau A Pathology, Hôpital Hôtel-Dieu, Nantes, France.
  • Sujobert P Faculté de Médecine Lyon-Sud Charles Mérieux, Université Claude Bernard, Lyon, France.
  • Pilichowska M Tufts University Medical Center, Boston, Massachusetts.
  • Evens AM Tufts University Medical Center, Boston, Massachusetts.
  • Chadburn A Presbyterian Hospital, Pathology and Cell Biology, Cornell University, New York, New York.
  • Au-Yeung RK University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
  • Srivastava G University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
  • Choi WW University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
  • Goodlad JR Department of Pathology, Western General Hospital, Edinburgh, UK.
  • Aurer I University Hospital Centre Zagreb, Zagreb, Croatia.
  • Basic-Kinda S University Hospital Centre Zagreb, Zagreb, Croatia.
  • Gascoyne RD British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada.
  • Davis NS Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
  • Li G Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
  • Zhang J Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
  • Rajagopalan D Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
  • Reddy A Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
  • Love C Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
  • Levy S Hudson Alpha Institute for Biotechnology, Huntsville, Alabama.
  • Zhuang Y Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
  • Datta J Department of Statistical Science, Duke University, Durham, North Carolina.
  • Dunson DB Department of Statistical Science, Duke University, Durham, North Carolina.
  • Davé SS Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina. ssd9@duke.edu.
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  • 2017-01-27
Published in:
  • Cancer discovery. - 2017
Adolescent
Adult
Aged
Base Sequence
Child
Child, Preschool
DNA Helicases
DNA-Binding Proteins
Enhancer of Zeste Homolog 2 Protein
Exome
Female
Histone-Lysine N-Methyltransferase
Humans
Liver Neoplasms
Lymphoma, T-Cell
Male
Middle Aged
Proto-Oncogene Proteins p21(ras)
Splenic Neoplasms
Transcription Factors
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Young Adult
English Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets.Significance: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease. Cancer Discov; 7(4); 369-79. ©2017 AACR.See related commentary by Yoshida and Weinstock, p. 352This article is highlighted in the In This Issue feature, p. 339.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/283538
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