Somatic mutations in histiocytic sarcoma identified by next generation sequencing.
Histiocytic sarcoma is a rare malignant neoplasm of presumed hematopoietic origin showing morphologic and immunophenotypic evidence of histiocytic differentiation. Somatic mutation importance in the pathogenesis or disease progression of histiocytic sarcoma was largely unknown. To identify somatic mutations in histiocytic sarcoma, we studied 5 histiocytic sarcomas [3 female and 2 male patients; mean age 54.8 (20-72), anatomic sites include lymph node, uterus, and pleura] and matched normal tissues from each patient as germ line controls. Somatic mutations in 50 "Hotspot" oncogenes and tumor suppressor genes were examined using next generation sequencing. Three (out of five) histiocytic sarcoma cases carried somatic mutations in BRAF. Among them, G464V [variant frequency (VF) of 43.6 %] and G466R (VF of 29.6 %) located at the P loop potentially interfere with the hydrophobic interaction between P and activating loops and ultimately activation of BRAF. Also detected was BRAF somatic mutation N581S (VF of 7.4 %), which was located at the catalytic loop of BRAF kinase domain: its role in modifying kinase activity was unclear. A similar mutational analysis was also performed on nine acute monocytic/monoblastic leukemia cases, which did not identify any BRAF somatic mutations. Our study detected several BRAF mutations in histiocytic sarcomas, which may be important in understanding the tumorigenesis of this rare neoplasm and providing mechanisms for potential therapeutical opportunities.
Department of Pathology, UMass Memorial Medical Center and University of Massachusetts Medical School, Worcester, MA, USA.|Department of Pathology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, USA.
Qingqing
Q
Liu
Department of Pathology, UMass Memorial Medical Center and University of Massachusetts Medical School, Worcester, MA, USA.
Keith
K
Tomaszewicz
Department of Pathology, UMass Memorial Medical Center and University of Massachusetts Medical School, Worcester, MA, USA.
Lloyd
L
Hutchinson
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Jason L
JL
Hornick
Department of Pathology, UMass Memorial Medical Center and University of Massachusetts Medical School, Worcester, MA, USA.
Bruce
B
Woda
Department of Pathology, UMass Memorial Medical Center and University of Massachusetts Medical School, Worcester, MA, USA. Hongbo.Yu@va.gov.|Pathology and Laboratory Medicine Service, VA Boston Healthcare System, 1400 VFW Parkway, West Roxbury, MA, 02132, USA. Hongbo.Yu@va.gov.
Hongbo
H
Yu
D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D054747:Histiocytic Sarcoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D016130:Immunophenotyping / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009857:Oncogenes / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012509:Sarcoma / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf
BRAF proto-oncogene; Histiocytic sarcoma; Next generation sequencing; Somatic mutations