title: ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma.
abstract: ALK oncogenic activation mechanisms were characterized in four conventional spindle-cell inflammatory myofibroblastic tumours (IMT) and five atypical IMT, each of which had ALK genomic perturbations. Constitutively activated ALK oncoproteins were purified by ALK immunoprecipitation and electrophoresis, and were characterized by mass spectrometry. The four conventional IMT had TPM3/4-ALK fusions (two cases) or DCTN1-ALK fusions (two cases), whereas two atypical spindle-cell IMT had TFG-ALK and TPM3-ALK fusion in one case each, and three epithelioid inflammatory myofibroblastic sarcomas had RANBP2-ALK fusions in two cases, and a novel RRBP1-ALK fusion in one case. The epithelioid inflammatory myofibroblastic sarcoma with RRBP1-ALK fusion had cytoplasmic ALK expression with perinuclear accentuation, different from the nuclear membranous ALK localization in epithelioid inflammatory myofibroblastic sarcomas with RANBP2-ALK fusions. Evaluation of three additional uncharacterized epithelioid inflammatory myofibroblastic sarcomas with ALK cytoplasmic/perinuclear- accentuation expression demonstrated RRBP1-ALK fusion in two cases. These studies show that atypical spindle-cell IMT can utilize the same ALK fusion mechanisms described previously in conventional IMT, whereas in clinically aggressive epithelioid inflammatory myofibroblastic sarcoma we identify a novel recurrent ALK oncogenic mechanism, resulting from fusion with the RRBP1 gene. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.|Bone and soft tissue study group, Taiwan Society of Pathology.
authors.forename: Jen-Chieh
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.|Bone and soft tissue study group, Taiwan Society of Pathology.
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Bone and soft tissue study group, Taiwan Society of Pathology.
authors.forename: Hsuan-Ying
authors.initials: HY
authors.lastname: Huang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, the United States.
authors.forename: Mei-Jun
authors.initials: MJ
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, the United States.
authors.forename: Adrián
authors.initials: A
authors.lastname: Mariño-Enríquez
authors.affiliation: Department of Pathology, National Cheng Kung University Hospital, Tainan City, Taiwan.
authors.forename: Chung-Ta
authors.initials: CT
authors.lastname: Lee
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, the United States.|Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.|Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, Zhejiang, China.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Ou
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, the United States.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, the United States.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002352:Carrier Proteins / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012509:Sarcoma / Q000235:genetics* / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D015513:Oncogene Proteins; C000602809:RRBP1 protein, human; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; RRBP1; epithelioid inflammatory myofibroblastic sarcoma; fusion gene; inflammatory myofibroblastic tumour; mass spectrometry