title: Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy.
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.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Churpek
authors.affiliation: Department of Medicine, Division of Hematology, University of Washington, Seattle, Washington, USA.
authors.forename: Siobán B
authors.initials: SB
authors.lastname: Keel
authors.affiliation: 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.
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.affiliation: 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.
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.affiliation: 1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2] Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Loeb
authors.affiliation: 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.
authors.forename: Suleyman
authors.initials: S
authors.lastname: Gulsuner
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Pritchard
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Sanchez-Bonilla
authors.affiliation: Genomics and Bioinformatics Shared Resources, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Delrow
authors.affiliation: Genomics and Bioinformatics Shared Resources, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Ryan S
authors.identifier: 0000000161371807
authors.initials: RS
authors.lastname: Basom
authors.affiliation: Pediatric Hematology Oncology, Madigan Army Medical Center, Tacoma, Washington, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Forouhar
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Boglarka
authors.initials: B
authors.lastname: Gyurkocza
authors.affiliation: 1] Morgridge Institute for Research, University of Wisconsin, Madison, Wisconsin, USA. [2] Departments of Medicine and Biomolecular Chemistry, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Bradford S
authors.initials: BS
authors.lastname: Schwartz
authors.affiliation: 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.
authors.forename: Barbara
authors.initials: B
authors.lastname: Neistadt
authors.affiliation: 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.
authors.forename: Rafael
authors.initials: R
authors.lastname: Marquez
authors.affiliation: 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.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Mariani
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Coats
authors.affiliation: 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.
authors.forename: Inga
authors.initials: I
authors.lastname: Hofmann
authors.affiliation: 1] Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA. [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: R Coleman
authors.initials: RC
authors.lastname: Lindsley
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
authors.affiliation: Department of Medicine, Division of Hematology, University of Washington, Seattle, Washington, USA.
authors.forename: Janis L
authors.initials: JL
authors.lastname: Abkowitz
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Marshall S
authors.initials: MS
authors.lastname: Horwitz
authors.affiliation: 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.
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.affiliation: 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.
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Godley
authors.affiliation: 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.
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamura
mesh_terms: D049109:Cell Proliferation; D005091:Exons / Q000235:genetics; D005260:Female; D017930:Genes, Reporter; D018095:Germ-Line Mutation; D006367:HeLa Cells; D019337:Hematologic Neoplasms / Q000235:genetics*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017434:Protein Structure, Tertiary; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D011994:Recombinant Proteins; D012097:Repressor Proteins / Q000235:genetics*; D017423:Sequence Analysis, RNA; D013921:Thrombocytopenia / Q000235:genetics*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050783:Proto-Oncogene Proteins c-ets; D011994:Recombinant Proteins; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein