G2Cdb::Human Disease report

Disease id
D00000005
Name
Low grade fibromyxoid sarcoma
Nervous system disease
no

Genes (1)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00002162 FUS
fused in sarcoma
Y (12915480) Translocation fusion (with another gene) (TF) Y
G00002162 FUS
fused in sarcoma
Y (15139001) Translocation fusion (with another gene) (TF) Y
G00002162 FUS
fused in sarcoma
Y (15640831) Translocation fusion (with another gene) (TF) Y
G00002162 FUS
fused in sarcoma
Y (16287497) Translocation fusion (with another gene) (TF) N
G00002162 FUS
fused in sarcoma
Y (16931951) Translocation fusion (with another gene) (TF) Y

References

  • Molecular detection of FUS-CREB3L2 fusion transcripts in low-grade fibromyxoid sarcoma using formalin-fixed, paraffin-embedded tissue specimens.

    Matsuyama A, Hisaoka M, Shimajiri S, Hayashi T, Imamura T, Ishida T, Fukunaga M, Fukuhara T, Minato H, Nakajima T, Yonezawa S, Kuroda M, Yamasaki F, Toyoshima S and Hashimoto H

    Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

    A diagnosis of low-grade fibromyxoid sarcoma (LGFMS) remains problematic because of its bland-looking histologic features that can be potentially confused with other benign or low-grade fibromyxoid lesions. Recent cytogenetic and molecular analyses have shown that most LGFMSs have a characteristic chromosomal abnormality, t(7;16)(q33;p11), resulting in the FUS-CREB3L2 fusion gene. However, such assays have only rarely been used to analyze formalin-fixed, paraffin-embedded tumor samples. In the present study, we conducted a reverse transcription-polymerase chain reaction assay to detect the FUS-CREB3L2 fusion transcripts using formalin-fixed, paraffin-embedded tumor tissue specimens from 16 LGFMSs including 3 cases with giant collagen rosettes. The primers were newly designed to specifically amplify most of the junctional regions of the FUS-CREB3L2 fusion gene transcripts previously reported. The FUS-CREB3L2 fusion gene transcripts were detected in 14/16 (88%) cases of LGFMS. A nucleotide sequence analysis of the PCR products revealed that different portions of the FUS exon 6 or 7 were fused with various sites of the CREB3L2 exon 5, resulting in 12 different nucleotide sequences. We also tested a primer set to detect the FUS-CREB3L1 fusion transcript, which is a rare variant of the gene fusion in LGFMS, although no PCR products were identified in any case. The FUS-CREB3L2 fusion transcripts were not detected in any of the 123 other soft-tissue tumors, including desmoid-type fibromatoses, myxofibrosarcomas, soft-tissue perineuriomas, and congenital or adult fibrosarcomas. These data suggest that our reverse transcription-polymerase chain reaction assay is a reliable method to detect FUS-CREB3L2, which can thus help in accurately diagnosing LGFMS.

    The American journal of surgical pathology 2006;30;9;1077-84

  • Low-grade fibromyxoid sarcoma arising in the big toe.

    Kusumi T, Nishikawa S, Tanaka M, Ogawa T, Jin H, Sato F, Toh S, Hasegawa T and Kijima H

    Department of Pathology, Hirosaki University School of Medicine, Hirosaki, Japan. kusumito@cc.hirosaki-u.ac.jp

    Low-grade fibromyxoid sarcoma (LGFMS) is a rare tumor. Reported herein is a case of LGFMS arising in the big toe. The patient was a 58-year-old man who underwent excision of the tumor. The tumor was well-demarcated. Histologically, there were proliferating spindle-shaped tumor cells arranged in a whorled growth pattern, and the stroma showed hyalinized collagen bundles and a myxoid matrix. Nuclear mitotic figures were conspicuous in part. A large rosette-like structure with hyalinized stroma was found, which is characteristic of LGFMS. The differential diagnosis included tumor occurrence in adults; tending to arise in distal extremities; and having bland fibromyxoid histological features, such as fibroma of tendon sheath, low-grade myxofibrosarcoma and acral myxoinflammatory fibroblastic sarcoma. It was not possible to detect the FUS/CREB3L2 and FUS/CREB3L1 fusion genes from the formalin-fixed and paraffin-embedded tissue, although the histological features of the present case were typical of LGFMS. LGFMS may become more common with time, and unique cases may accumulate.

    Pathology international 2005;55;12;802-6

  • Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene.

    Mertens F, Fletcher CD, Antonescu CR, Coindre JM, Colecchia M, Domanski HA, Downs-Kelly E, Fisher C, Goldblum JR, Guillou L, Reid R, Rosai J, Sciot R, Mandahl N and Panagopoulos I

    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden. fredrik.mertens@klingen.lu.se

    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.

    Laboratory investigation; a journal of technical methods and pathology 2005;85;3;408-15

  • The chimeric FUS/CREB3l2 gene is specific for low-grade fibromyxoid sarcoma.

    Panagopoulos I, Storlazzi CT, Fletcher CD, Fletcher JA, Nascimento A, Domanski HA, Wejde J, Brosjö O, Rydholm A, Isaksson M, Mandahl N and Mertens F

    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.

    Low-grade fibromyxoid sarcoma (LGFMS) is a variant of fibrosarcoma that was recognized as a distinct tumor entity only quite recently. We previously described a translocation, t(7;16)(q33;p11), that resulted in a fusion of the FUS and CREB3L2 (also known as BBF2H7) genes in two soft tissue tumors that fulfilled morphologic criteria for LGFMS. To delineate the spectrum of tumors that may harbor the FUS/CREB3L2 gene, we selected 45 low-grade spindle cell sarcomas for reverse transcriptase polymerase chain reaction (RT-PCR) and/or fluorescence in situ hybridization (FISH) analyses; none of these tumors had originally been diagnosed as LGFMS. Furthermore, also included were two benign soft tissue tumors and nine high-grade sarcomas with supernumerary ring chromosomes or 7q3 rearrangement and three tumors diagnosed as LGFMS prior to the genetic analysis. Of the 59 tumors analyzed, 12 were FUS/CREB3L2-positive, all of which were diagnosed at histopathologic re-examination as being LGFMS, of both the classical subtype and the subtype with giant collagen rosettes. The breakpoints in the fusion transcripts were always in exons 6 or 7 of FUS and exon 5 of CREB3L2. The results indicated that FUS/CREB3L2 is specifically associated with LGFMS and that RT-PCR or FISH analysis may be useful for the differential diagnosis.

    Genes, chromosomes & cancer 2004;40;3;218-28

  • Fusion of the FUS and BBF2H7 genes in low grade fibromyxoid sarcoma.

    Storlazzi CT, Mertens F, Nascimento A, Isaksson M, Wejde J, Brosjo O, Mandahl N and Panagopoulos I

    Department of Clinical Genetics, University Hospital, Lund, Sweden.

    The FUS gene at 16p11 fuses with DDIT3 and ATF1 as the result of translocations with chromosome band 12q13 in myxoid liposarcoma and angiomatoid fibrous histiocytoma, respectively, and with ERG as the result of a t(16;21)(p11;q22) in acute myeloid leukemia. We here show that a t(7;16)(q33;p11) in two cases of low grade fibromyxoid sarcoma fuses the FUS gene to BBF2H7, a previously uncharacterized gene that is homologous to the Drosophila Bbf-2 gene. BBF2H7 spans more than 120 kbp genomic DNA, is composed of 12 exons and contains a 1560 bp open reading frame. It codes for a 519 amino acid protein that contains a basic DNA binding and leucine zipper dimerization (B-ZIP) motif, highly similar to that in the OASIS, CREB-H, CREB4 and CREB3 transcription factors, followed by a hydrophobic region predicted to be an alpha-helical transmembrane domain. Reverse transcription-polymerase chain reaction (RT-PCR), using FUS forward and BBF2H7 reverse primers, amplified FUS/BBF2H7 chimeric transcripts composed of the first five exons and part of exon 6 of FUS and part of exon 5 and exons 6-12 of BBF2H7. The FUS/BBF2H7 chimera codes for a protein containing the N-terminus of FUS and the B-ZIP domain and the C-terminus of BBF2H7.

    Human molecular genetics 2003;12;18;2349-58

Literature (5)

Pubmed - human_disease

  • Molecular detection of FUS-CREB3L2 fusion transcripts in low-grade fibromyxoid sarcoma using formalin-fixed, paraffin-embedded tissue specimens.

    Matsuyama A, Hisaoka M, Shimajiri S, Hayashi T, Imamura T, Ishida T, Fukunaga M, Fukuhara T, Minato H, Nakajima T, Yonezawa S, Kuroda M, Yamasaki F, Toyoshima S and Hashimoto H

    Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

    A diagnosis of low-grade fibromyxoid sarcoma (LGFMS) remains problematic because of its bland-looking histologic features that can be potentially confused with other benign or low-grade fibromyxoid lesions. Recent cytogenetic and molecular analyses have shown that most LGFMSs have a characteristic chromosomal abnormality, t(7;16)(q33;p11), resulting in the FUS-CREB3L2 fusion gene. However, such assays have only rarely been used to analyze formalin-fixed, paraffin-embedded tumor samples. In the present study, we conducted a reverse transcription-polymerase chain reaction assay to detect the FUS-CREB3L2 fusion transcripts using formalin-fixed, paraffin-embedded tumor tissue specimens from 16 LGFMSs including 3 cases with giant collagen rosettes. The primers were newly designed to specifically amplify most of the junctional regions of the FUS-CREB3L2 fusion gene transcripts previously reported. The FUS-CREB3L2 fusion gene transcripts were detected in 14/16 (88%) cases of LGFMS. A nucleotide sequence analysis of the PCR products revealed that different portions of the FUS exon 6 or 7 were fused with various sites of the CREB3L2 exon 5, resulting in 12 different nucleotide sequences. We also tested a primer set to detect the FUS-CREB3L1 fusion transcript, which is a rare variant of the gene fusion in LGFMS, although no PCR products were identified in any case. The FUS-CREB3L2 fusion transcripts were not detected in any of the 123 other soft-tissue tumors, including desmoid-type fibromatoses, myxofibrosarcomas, soft-tissue perineuriomas, and congenital or adult fibrosarcomas. These data suggest that our reverse transcription-polymerase chain reaction assay is a reliable method to detect FUS-CREB3L2, which can thus help in accurately diagnosing LGFMS.

    The American journal of surgical pathology 2006;30;9;1077-84

  • Low-grade fibromyxoid sarcoma arising in the big toe.

    Kusumi T, Nishikawa S, Tanaka M, Ogawa T, Jin H, Sato F, Toh S, Hasegawa T and Kijima H

    Department of Pathology, Hirosaki University School of Medicine, Hirosaki, Japan. kusumito@cc.hirosaki-u.ac.jp

    Low-grade fibromyxoid sarcoma (LGFMS) is a rare tumor. Reported herein is a case of LGFMS arising in the big toe. The patient was a 58-year-old man who underwent excision of the tumor. The tumor was well-demarcated. Histologically, there were proliferating spindle-shaped tumor cells arranged in a whorled growth pattern, and the stroma showed hyalinized collagen bundles and a myxoid matrix. Nuclear mitotic figures were conspicuous in part. A large rosette-like structure with hyalinized stroma was found, which is characteristic of LGFMS. The differential diagnosis included tumor occurrence in adults; tending to arise in distal extremities; and having bland fibromyxoid histological features, such as fibroma of tendon sheath, low-grade myxofibrosarcoma and acral myxoinflammatory fibroblastic sarcoma. It was not possible to detect the FUS/CREB3L2 and FUS/CREB3L1 fusion genes from the formalin-fixed and paraffin-embedded tissue, although the histological features of the present case were typical of LGFMS. LGFMS may become more common with time, and unique cases may accumulate.

    Pathology international 2005;55;12;802-6

  • Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene.

    Mertens F, Fletcher CD, Antonescu CR, Coindre JM, Colecchia M, Domanski HA, Downs-Kelly E, Fisher C, Goldblum JR, Guillou L, Reid R, Rosai J, Sciot R, Mandahl N and Panagopoulos I

    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden. fredrik.mertens@klingen.lu.se

    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.

    Laboratory investigation; a journal of technical methods and pathology 2005;85;3;408-15

  • The chimeric FUS/CREB3l2 gene is specific for low-grade fibromyxoid sarcoma.

    Panagopoulos I, Storlazzi CT, Fletcher CD, Fletcher JA, Nascimento A, Domanski HA, Wejde J, Brosjö O, Rydholm A, Isaksson M, Mandahl N and Mertens F

    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.

    Low-grade fibromyxoid sarcoma (LGFMS) is a variant of fibrosarcoma that was recognized as a distinct tumor entity only quite recently. We previously described a translocation, t(7;16)(q33;p11), that resulted in a fusion of the FUS and CREB3L2 (also known as BBF2H7) genes in two soft tissue tumors that fulfilled morphologic criteria for LGFMS. To delineate the spectrum of tumors that may harbor the FUS/CREB3L2 gene, we selected 45 low-grade spindle cell sarcomas for reverse transcriptase polymerase chain reaction (RT-PCR) and/or fluorescence in situ hybridization (FISH) analyses; none of these tumors had originally been diagnosed as LGFMS. Furthermore, also included were two benign soft tissue tumors and nine high-grade sarcomas with supernumerary ring chromosomes or 7q3 rearrangement and three tumors diagnosed as LGFMS prior to the genetic analysis. Of the 59 tumors analyzed, 12 were FUS/CREB3L2-positive, all of which were diagnosed at histopathologic re-examination as being LGFMS, of both the classical subtype and the subtype with giant collagen rosettes. The breakpoints in the fusion transcripts were always in exons 6 or 7 of FUS and exon 5 of CREB3L2. The results indicated that FUS/CREB3L2 is specifically associated with LGFMS and that RT-PCR or FISH analysis may be useful for the differential diagnosis.

    Genes, chromosomes & cancer 2004;40;3;218-28

Pubmed - other

  • Fusion of the FUS and BBF2H7 genes in low grade fibromyxoid sarcoma.

    Storlazzi CT, Mertens F, Nascimento A, Isaksson M, Wejde J, Brosjo O, Mandahl N and Panagopoulos I

    Department of Clinical Genetics, University Hospital, Lund, Sweden.

    The FUS gene at 16p11 fuses with DDIT3 and ATF1 as the result of translocations with chromosome band 12q13 in myxoid liposarcoma and angiomatoid fibrous histiocytoma, respectively, and with ERG as the result of a t(16;21)(p11;q22) in acute myeloid leukemia. We here show that a t(7;16)(q33;p11) in two cases of low grade fibromyxoid sarcoma fuses the FUS gene to BBF2H7, a previously uncharacterized gene that is homologous to the Drosophila Bbf-2 gene. BBF2H7 spans more than 120 kbp genomic DNA, is composed of 12 exons and contains a 1560 bp open reading frame. It codes for a 519 amino acid protein that contains a basic DNA binding and leucine zipper dimerization (B-ZIP) motif, highly similar to that in the OASIS, CREB-H, CREB4 and CREB3 transcription factors, followed by a hydrophobic region predicted to be an alpha-helical transmembrane domain. Reverse transcription-polymerase chain reaction (RT-PCR), using FUS forward and BBF2H7 reverse primers, amplified FUS/BBF2H7 chimeric transcripts composed of the first five exons and part of exon 6 of FUS and part of exon 5 and exons 6-12 of BBF2H7. The FUS/BBF2H7 chimera codes for a protein containing the N-terminus of FUS and the B-ZIP domain and the C-terminus of BBF2H7.

    Human molecular genetics 2003;12;18;2349-58

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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