Identification of ZCCHC8 as fusion partner of ROS1 in a case of congenital glioblastoma multiforme with a t(6;12)(q21;q24.3).
Congenital gliobastoma multiforme (GBM) is rare and little is known about the molecular defects underlying the initiation and progression of this tumor type. We present a case of congenital GBM analyzed by conventional cytogenetics, fluorescence in situ hybridization, array comparative genomic hybridization and next generation sequencing. On cytogenetic analysis we detected a reciprocal translocation t(6;12)(q21;q24.3). By sequencing, the translocation was shown to form a fusion between the 5' region of ZCCHC8 and the 3' region of ROS1. RT-PCR analyses confirmed the existence of an in-frame fusion transcript with ZCCHC8 exons 1-3 joined to ROS1 exons 36-43. In addition to the ZCCHC8-ROS1 fusion, we detected a deletion in the short arm of chromosome 9, including homozygous loss of the CDKN2A/2B locus in 9p21.3 and heterozygous deletion of the HAUS6 gene in 9p22.1. The latter encodes a protein involved in faithful chromosome segregation by regulating microtubule nucleation and its deletion might be associated with the marked subclonal changes of ploidy observed in the tumor. This report adds the ZCCHC8-ROS1 fusion as oncogenic driver in GBM and supports the role of ROS1 activation in the pathogenesis of a subset of GBM. © 2016 Wiley Periodicals, Inc.
Cytogenetics Laboratory, Genetics Department, Garrahan Pediatrics Hospital, Buenos Aires, Argentina.
Mariela C
MC
Coccé
Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
Balca R
BR
Mardin
Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Kiel, Germany.
Susanne
S
Bens
Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
Adrian M
AM
Stütz
Pathology Department, Garrahan Pediatrics Hospital, Buenos Aires, Argentina.
Fabiana
F
Lubieniecki
Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Kiel, Germany.
Inga
I
Vater
Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
Jan O
JO
Korbel
Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Kiel, Germany.
Reiner
R
Siebert
Laboratory of Molecular Biology, Hematology and Oncology Department, Garrahan Pediatrics Hospital, Buenos Aires, Argentina.
Cristina N
CN
Alonso
Cytogenetics Laboratory, Genetics Department, Garrahan Pediatrics Hospital, Buenos Aires, Argentina.
Marta S
MS
Gallego
D002352:Carrier Proteins / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D020732:Cytogenetic Analysis; D005909:Glioblastoma / Q000151:congenital* / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic / Q000235:genetics*
D002352:Carrier Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; C506699:ZCCHC8 protein, human; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human