title: BRCC3 mutations in myeloid neoplasms.
abstract: Next generation sequencing technologies have provided insights into the molecular heterogeneity of various myeloid neoplasms, revealing previously unknown somatic genetic events. In our cohort of 1444 cases analyzed by next generation sequencing, somatic mutations in the gene BRCA1-BRCA2-containing complex 3 (BRCC3) were identified in 28 cases (1.9%). BRCC3 is a member of the JAMM/MPN+ family of zinc metalloproteases capable of cleaving Lys-63 linked polyubiquitin chains, and is implicated in DNA repair. The mutations were located throughout its coding region. The average variant allelic frequency of BRCC3 mutations was 30.1%, and by a serial sample analysis at two different time points a BRCC3 mutation was already identified in the initial stage of a myelodysplastic syndrome. BRCC3 mutations commonly occurred in nonsense (n=12), frameshift (n=4), and splice site (n=5) configurations. Due to the marginal male dominance (odds ratio; 2.00, 0.84-4.73) of BRCC3 mutations, the majority of mutations (n=23; 82%) were hemizygous. Phenotypically, BRCC3 mutations were frequently observed in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms and associated with -Y abnormality (odds ratio; 3.70, 1.25-11.0). Clinically, BRCC3 mutations were also related to higher age (P=0.01), although prognosis was not affected. Knockdown of Brcc3 gene expression in murine bone marrow lineage negative, Sca1 positive, c-kit positive cells resulted in 2-fold more colony formation and modest differentiation defect. Thus, BRCC3 likely plays a role as tumor-associated gene in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms.
authors.affiliation: Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Dayong
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nagata
authors.affiliation: Munich Leukemia Laboratory (MLL), Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Grossmann
authors.affiliation: Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, OH, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Radivoyevitch
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Japan.
authors.forename: Genta
authors.initials: G
authors.lastname: Nagae
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Naoko
authors.initials: N
authors.lastname: Hosono
authors.affiliation: Munich Leukemia Laboratory (MLL), Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Przychodzen
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Japan.
authors.forename: Ayana
authors.initials: A
authors.lastname: Kon
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Chantana
authors.initials: C
authors.lastname: Polprasert
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Shen
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clemente
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Phillips
authors.affiliation: Munich Leukemia Laboratory (MLL), Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Alpermann
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Munich Leukemia Laboratory (MLL), Germany.
authors.forename: Niroshan
authors.initials: N
authors.lastname: Nadarajah
authors.affiliation: Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, OH, USA.
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.affiliation: Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Oakley
authors.affiliation: Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors.forename: Nhu
authors.initials: N
authors.lastname: Nguyen
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shiozawa
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA Cancer Science Institute of Singapore, National University of Singapore.
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.affiliation: Institute of Medical Informatics, University of Münster, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Klein
authors.affiliation: Institute of Medical Informatics, University of Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Dugas
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Japan Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Munich Leukemia Laboratory (MLL), Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Haferlach
authors.affiliation: Munich Leukemia Laboratory (MLL), Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kern
authors.affiliation: Munich Leukemia Laboratory (MLL), Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA Department of Pathology and Tumor Biology, Kyoto University, Japan makishimah@gmail.com.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics; D002869:Chromosome Aberrations; D004252:DNA Mutational Analysis; D000072017:Deubiquitinating Enzymes; D005260:Female; D005787:Gene Frequency; D055785:Gene Knockdown Techniques; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C518017:BRCC3 protein, human; D000072017:Deubiquitinating Enzymes