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Haematologica. 2015 Aug;100(8):1051-7. doi: 10.3324/haematol.2014.111989. Epub 2015 May 22.

BRCC3 mutations in myeloid neoplasms.

Author information

  • 1Department 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.
  • 2Department of Pathology and Tumor Biology, Kyoto University, Japan.
  • 3Munich Leukemia Laboratory (MLL), Germany.
  • 4Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, OH, USA.
  • 5Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Japan.
  • 6Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
  • 7Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, OH, USA.
  • 8Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
  • 9Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Japan.
  • 10Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Japan.
  • 11Department of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA Cancer Science Institute of Singapore, National University of Singapore.
  • 12Institute of Medical Informatics, University of M├╝nster, Germany.
  • 13Laboratory 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.
  • 14Department 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.

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.

Copyright┬ę Ferrata Storti Foundation.

PMID:
26001790
[PubMed - indexed for MEDLINE]
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