title: Fusion genes with ALK as recurrent partner in ependymoma-like gliomas: a new brain tumor entity?
abstract: BACKGROUND
  We have previously characterized 19 ependymal tumors using Giemsa banding and high-resolution comparative genomic hybridization. The aim of this study was to analyze these tumors searching for fusion genes.
  
  
  METHODS
  RNA sequencing was performed in 12 samples. Potential fusion transcripts were assessed by seed count and structural chromosomal aberrations. Transcripts of interest were validated using fluorescence in situ hybridization and PCR followed by direct sequencing.
  
  
  RESULTS
  RNA sequencing identified rearrangements of the anaplastic lymphoma kinase gene (ALK) in 2 samples. Both tumors harbored structural aberrations involving the ALK locus 2p23. Tumor 1 had an unbalanced t(2;14)(p23;q22) translocation which led to the fusion gene KTN1-ALK. Tumor 2 had an interstitial del(2)(p16p23) deletion causing the fusion of CCDC88A and ALK. In both samples, the breakpoint of ALK was located between exons 19 and 20. Both patients were infants and both tumors were supratentorial. The tumors were well demarcated from surrounding tissue and had both ependymal and astrocytic features but were diagnosed and treated as ependymomas.
  
  
  CONCLUSIONS
  By combining karyotyping and RNA sequencing, we identified the 2 first ever reported ALK rearrangements in CNS tumors. Such rearrangements may represent the hallmark of a new entity of pediatric glioma characterized by both ependymal and astrocytic features. Our findings are of particular importance because crizotinib, a selective ALK inhibitor, has demonstrated effect in patients with lung cancer harboring ALK rearrangements. Thus, ALK emerges as an interesting therapeutic target in patients with ependymal tumors carrying ALK fusions.
authors: Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., S.H.); Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway (T.R.M., B.D.-T.); Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway (M.L.-I., B.K.); Department of Radiology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (C.S.); Department of Pathology, Rigshospitalet, Copenhagen, Denmark (D.S.); Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (P.B.).
authors: Thale Kristin
authors: TK
authors: Olsen
authors: Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., S.H.); Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway (T.R.M., B.D.-T.); Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway (M.L.-I., B.K.); Department of Radiology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (C.S.); Department of Pathology, Rigshospitalet, Copenhagen, Denmark (D.S.); Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (P.B.).
authors: Ioannis
authors: I
authors: Panagopoulos
authors: Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., S.H.); Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway (T.R.M., B.D.-T.); Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway (M.L.-I., B.K.); Department of Radiology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (C.S.); Department of Pathology, Rigshospitalet, Copenhagen, Denmark (D.S.); Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (P.B.).
authors: Torstein R
authors: TR
authors: Meling
authors: Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., S.H.); Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway (T.R.M., B.D.-T.); Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway (M.L.-I., B.K.); Department of Radiology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (C.S.); Department of Pathology, Rigshospitalet, Copenhagen, Denmark (D.S.); Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (P.B.).
authors: Francesca
authors: F
authors: Micci
authors: Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., S.H.); Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway (T.R.M., B.D.-T.); Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway (M.L.-I., B.K.); Department of Radiology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (C.S.); Department of Pathology, Rigshospitalet, Copenhagen, Denmark (D.S.); Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (P.B.).
authors: Ludmila
authors: L
authors: Gorunova
authors: Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., S.H.); Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway (T.R.M., B.D.-T.); Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway (M.L.-I., B.K.); Department of Radiology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (C.S.); Department of Pathology, Rigshospitalet, Copenhagen, Denmark (D.S.); Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (P.B.).
authors: Jim
authors: J
authors: Thorsen
authors: Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., S.H.); Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway (T.R.M., B.D.-T.); Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway (M.L.-I., B.K.); Department of Radiology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (C.S.); Department of Pathology, Rigshospitalet, Copenhagen, Denmark (D.S.); Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (P.B.).
authors: Bernt
authors: B
authors: Due-Tønnessen
authors: Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., S.H.); Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway (T.R.M., B.D.-T.); Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway (M.L.-I., B.K.); Department of Radiology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (C.S.); Department of Pathology, Rigshospitalet, Copenhagen, Denmark (D.S.); Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (P.B.).
authors: David
authors: D
authors: Scheie
authors: Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., S.H.); Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway (T.R.M., B.D.-T.); Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway (M.L.-I., B.K.); Department of Radiology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (C.S.); Department of Pathology, Rigshospitalet, Copenhagen, Denmark (D.S.); Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (P.B.).
authors: Marius
authors: M
authors: Lund-Iversen
authors: Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., S.H.); Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway (T.R.M., B.D.-T.); Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway (M.L.-I., B.K.); Department of Radiology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (C.S.); Department of Pathology, Rigshospitalet, Copenhagen, Denmark (D.S.); Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (P.B.).
authors: Bård
authors: B
authors: Krossnes
authors: Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., S.H.); Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway (T.R.M., B.D.-T.); Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway (M.L.-I., B.K.); Department of Radiology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (C.S.); Department of Pathology, Rigshospitalet, Copenhagen, Denmark (D.S.); Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (P.B.).
authors: Cathrine
authors: C
authors: Saxhaug
authors: Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., S.H.); Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway (T.R.M., B.D.-T.); Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway (M.L.-I., B.K.); Department of Radiology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (C.S.); Department of Pathology, Rigshospitalet, Copenhagen, Denmark (D.S.); Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (P.B.).
authors: Sverre
authors: S
authors: Heim
authors: Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., I.P., F.M., L.G., J.T., S.H., P.B.); Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (T.K.O., S.H.); Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway (T.R.M., B.D.-T.); Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway (M.L.-I., B.K.); Department of Radiology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (C.S.); Department of Pathology, Rigshospitalet, Copenhagen, Denmark (D.S.); Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway (P.B.).
authors: Petter
authors: P
authors: Brandal
mesh_terms: D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D004806:Ependymoma / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D007621:Karyotyping; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017423:Sequence Analysis, RNA; D033921:Vesicular Transport Proteins / Q000235:genetics
chemical_list: C502451:CCDC88A protein, human; C088547:KTN1 protein, human; D008565:Membrane Proteins; D008840:Microfilament Proteins; D015514:Oncogene Proteins, Fusion; D033921:Vesicular Transport Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: RNA sequencing; anaplastic lymphoma kinase; chromosomal aberrations; ependymoma; fusion genes