title: GRM1 is upregulated through gene fusion and promoter swapping in chondromyxoid fibroma.
abstract: Glutamate receptors are well-known actors in the central and peripheral nervous systems, and altered glutamate signaling is implicated in several neurological and psychiatric disorders. It is increasingly recognized that such receptors may also have a role in tumor growth. Here we provide direct evidence of aberrant glutamate signaling in the development of a locally aggressive bone tumor, chondromyxoid fibroma (CMF). We subjected a series of CMFs to whole-genome mate-pair sequencing and RNA sequencing and found that the glutamate receptor gene GRM1 recombines with several partner genes through promoter swapping and gene fusion events. The GRM1 coding region remains intact, and 18 of 20 CMFs (90%) showed a more than 100-fold and up to 1,400-fold increase in GRM1 expression levels compared to control tissues. Our findings unequivocally demonstrate that direct targeting of GRM1 is a necessary and highly specific driver event for CMF development.
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Karolin H
authors.initials: KH
authors.lastname: Nord
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Lilljebjörn
authors.affiliation: Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden.
authors.forename: Francesco
authors.initials: F
authors.lastname: Vezzi
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Nilsson
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Magnusson
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Johnbosco
authors.initials: J
authors.lastname: Tayebwa
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Danielle
authors.initials: D
authors.lastname: de Jong
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Judith V M G
authors.initials: JV
authors.lastname: Bovée
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Karoly
authors.initials: K
authors.lastname: Szuhai
mesh_terms: D001483:Base Sequence; D001859:Bone Neoplasms / Q000235:genetics*; D002871:Chromosome Banding; D056915:DNA Copy Number Variations; D005350:Fibroma / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D050939:Gene Fusion / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008969:Molecular Sequence Data; D009426:Netherlands; D011401:Promoter Regions, Genetic / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D018094:Receptors, Metabotropic Glutamate