title: Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene.
abstract: Low-grade fibromyxoid sarcoma (LGFMS) is an indolent, late-metastasizing malignant soft-tissue tumor that is often mistaken for either more benign or more malignant tumor types. Cytogenetic analyses have identified a recurrent balanced translocation t(7;16) (q32-34;p11), later shown by molecular genetic approaches to result in a FUS/CREB3L2 fusion gene. Whereas preliminary studies suggest that this gene rearrangement is specific for LGFMS, its incidence in this tumor type and the possible existence of variant fusion genes have not yet been addressed. For this purpose, a series of potential LGFMS were obtained from nine different soft-tissue tumor centres and subjected to molecular analysis as well as careful histopathologic review. Reverse transcriptase-polymerase chain reaction analysis disclosed a FUS/CREB3L2 fusion transcript in 22 of the 23 (96%) cases that remained classified as LGFMS after the histologic re-evaluation and from which RNA of sufficient quality could be extracted, whereas none of the cases that were classified as other tumor types was fusion-positive. In one of the tumors with typical LGFMS appearance, we found that FUS was fused to the CREB3L1 gene instead of CREB3L2. The proteins encoded by these genes both belong to the same basic leucine-zipper family of transcription factors, and display extensive sequence homology in their DNA-binding domains. Thus, it is expected that the novel FUS/CREB3L1 chimera will have a similar impact at the cellular level as the much more common FUS/CREB3L2 fusion protein. Taken together, the results indicate that virtually all LGFMS are characterized by a chimeric FUS/CREB3L2 gene, and that rare cases may display a variant FUS/CREB3L1 fusion.
authors.affiliation: Department of Clinical Genetics, Lund University Hospital, Lund, Sweden. fredrik.mertens@klingen.lu.se
authors.forename: Fredrik
authors.initials: F
authors.lastname: Mertens
authors.forename: Christopher D M
authors.initials: CD
authors.lastname: Fletcher
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.forename: Maurizio
authors.initials: M
authors.lastname: Colecchia
authors.forename: Henryk A
authors.initials: HA
authors.lastname: Domanski
authors.forename: Erinn
authors.initials: E
authors.lastname: Downs-Kelly
authors.forename: Cyril
authors.initials: C
authors.lastname: Fisher
authors.forename: John R
authors.initials: JR
authors.lastname: Goldblum
authors.forename: Louis
authors.initials: L
authors.lastname: Guillou
authors.forename: Robin
authors.initials: R
authors.lastname: Reid
authors.forename: Juan
authors.initials: J
authors.lastname: Rosai
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Nils
authors.initials: N
authors.lastname: Mandahl
authors.forename: Ioannis
authors.initials: I
authors.lastname: Panagopoulos
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein; D003937:Diagnosis, Differential; D005260:Female; D005354:Fibrosarcoma / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D034702:RNA-Binding Protein FUS / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012983:Soft Tissue Neoplasms / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D014408:Biomarkers, Tumor; C485618:CREB3L1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D034702:RNA-Binding Protein FUS; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors