2. Academic Validation
  3. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy

Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy

  • Nat Genet. 2015 Feb;47(2):180-5. doi: 10.1038/ng.3177.
Michael Y Zhang 1,  Jane E Churpek 2,  Siobán B Keel 3,  Tom Walsh 4,  Ming K Lee 4,  Keith R Loeb 5,  Suleyman Gulsuner 4,  Colin C Pritchard 6,  Marilyn Sanchez-Bonilla 1,  Jeffrey J Delrow 7,  Ryan S Basom 7,  Melissa Forouhar 8,  Boglarka Gyurkocza 1,  Bradford S Schwartz 9,  Barbara Neistadt 2,  Rafael Marquez 2,  Christopher J Mariani 2,  Scott A Coats 1,  Inga Hofmann 10,  R Coleman Lindsley 11,  David A Williams 10,  Janis L Abkowitz 3,  Marshall S Horwitz 12,  Mary-Claire King 4,  Lucy A Godley 2,  Akiko Shimamura 13
Affiliations

Affiliations

  • 1 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  • 2 1] Section of Hematology/Oncology, Center for Clinical Cancer Genetics, University of Chicago, Chicago, Illinois, USA. [2] Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, USA.
  • 3 Department of Medicine, Division of Hematology, University of Washington, Seattle, Washington, USA.
  • 4 1] Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington, USA. [2] Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
  • 5 1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2] Department of Pathology, University of Washington, Seattle, Washington, USA.
  • 6 Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
  • 7 Genomics and Bioinformatics Shared Resources, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  • 8 Pediatric Hematology Oncology, Madigan Army Medical Center, Tacoma, Washington, USA.
  • 9 1] Morgridge Institute for Research, University of Wisconsin, Madison, Wisconsin, USA. [2] Departments of Medicine and Biomolecular Chemistry, University of Wisconsin, Madison, Wisconsin, USA.
  • 10 1] Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School Boston, Massachusetts, USA. [2] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [3] Harvard Stem Cell Institute, Boston, Massachusetts, USA.
  • 11 1] Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA. [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 12 Department of Pathology, University of Washington, Seattle, Washington, USA.
  • 13 1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2] Pediatric Hematology/Oncology, Seattle Children's Hospital, Seattle, Washington, USA. [3] Department of Pediatrics, University of Washington, Seattle, Washington, USA.
PMID: 25581430 DOI: 10.1038/ng.3177
Abstract

We report germline missense mutations in ETV6 segregating with the dominant transmission of thrombocytopenia and hematologic malignancy in three unrelated kindreds, defining a new hereditary syndrome featuring thrombocytopenia with susceptibility to diverse hematologic neoplasms. Two variants, p.Arg369Gln and p.Arg399Cys, reside in the highly conserved ETS DNA-binding domain. The third variant, p.Pro214Leu, lies within the internal linker domain, which regulates DNA binding. These three amino acid sites correspond to hotspots for recurrent somatic mutation in malignancies. Functional studies show that the mutations abrogate DNA binding, alter subcellular localization, decrease transcriptional repression in a dominant-negative fashion and impair hematopoiesis. These familial genetic studies identify a central role for ETV6 in hematopoiesis and malignant transformation. The identification of germline predisposition to cytopenias and Cancer informs the diagnosis and medical management of at-risk individuals.

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