Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

Soft Tissue Tumors: Liposarcoma: Myxoid liposarcoma

Identity

Phylum Soft Tissue Tumors:Liposarcoma:Myxoid liposarcoma
Other namesMyxoid-round cell liposarcoma
Note Sarcomas are relatively rare malignant tumours and comprise less than 10% of all cancers. Classical classifications of sarcomas are based on the site of tumour (bone or soft tissue). Soft tissue sarcoma (STS) is the collective term used for malignancies arising in muscles, fat, vessels, the peripheral nervous system and fibrous tissue. Histopathologic examination of such tumours has revealed a large number of distinct entities, each displaying its own morphologic and clinical characteristics. Cytogenetic and molecular genetic analyses have shown that some of these STS are characterized by specific chromosomal translocations, whereas other STS show complex genetic aberrations.
Liposarcoma is the most common soft tissue malignancy in adults accounting for at least 20% of all sarcomas in this age group. Myxoid-round cell liposarcoma is a subtype of liposarcoma characterized by the presence of the reciprocal chromosomal translocation t(12;16)(q13;p11). This translocation creates the FUS-DDIT3 chimeric gene.

Classification

    Liposarcoma is a lipogenic tumour subclassified into four main histologic groups, including well-differentiated liposarcoma (lipoma-like and sclerosing types), myxoid-round cell liposarcoma, pleomorphic liposarcoma, and dedifferentiated liposarcoma. The histologic group is predictive of both the clinical course of the disease and the ultimate prognosis.

Clinics and Pathology

 

Cytogenetics

Cytogenetics
Morphological
Cytogenetics analyses have shown that several lipogenic tumours are characterized by specific chromosomal abnormalities, the best known was the reciprocal translocation t(12;16)(q13;p11) of myxoid-round cell liposarcoma, described about twenty years ago.This translocation results in a fusion gene consisting of the 5' part of the FUS (TLS) gene and the complete coding region of the CHOP gene (see fig.1).

Genes involved and Proteins

Gene Name FUS (TLS)
Location 16p11
Dna / Rna The FUS gene consists of 15 exons located within 11 kb of genomic DNA, and the exon 1 contains a 72-bp untranslated region and the translation initiation codon. The location of the FUS gene was identified as 16p11 by the site of the breakpoint in the translocation. The assignment was further narrowed to 16p11.2 by cytogenetic studies. FUS is rearranged in myxoid liposarcomas in the characteristic chromosomal translocation t(12;16)(q13;p11).
Protein The FUS protein, provisionally designated TLS (translocated in liposarcoma), and then called FUS, contains an RNA-recognition motif and is a component of nuclear riboprotein complexes. Lack of FUS in mice causes lethallity into neonatal period, it influences lymphocyte development in a non-cell-intrinsic manner, it has an intrinsic role in the proliferative responses of B cells to specific mitogenic stimuli, and it is required for the maintenance of genomic stability. The involvement of a nuclear riboprotein in these processes in vivo indicates that FUS is important in genome maintenance.
Somatic mutation Variants: FUS has been also shown a partner of gene fusions linked in other malignances: fused to ERG in acute myeloid leukaemia with t(16:21)(p11;q22), fused to CREB3L2 in low-grade fibromyxoid .sarcoma (LGFMS) by a translocation between chromosome bands 7q33-q34 (CREB3L2) and 16p11 (FUS) or fused to ATF1 in histiocytoma.

Gene Name DDIT3 (CHOP)
Location 12q13
Dna / Rna The DDIT3 gene was isolated from human cells and has a high level of conservation with previously described hamster gene. Each is composed of 4 exons with intron/exon junctions maintained at identical positions. They showed 91% identity in amino acid sequence and 78% identity in nucleotide sequence. The gene is located on chromosome 12 (12q13.1-q13.2)
Protein CHOP (C/EBP-homologous protein) is a nuclear protein which was identified as a dominant-negative inhibitor of the transcription factors C/EBP and LAP. The protein also was called DDIT3 for DNA damage-inducible transcript 3' and GADD153 for 'growth arrest- and DNA damage-inducible gene. DDIT3 is consistently rearranged in myxoid liposarcomas in the characteristic chromosomal translocation t(12;16)(q13;p11). Its molecular characterization showed that the DDIT3 gene is fused with a gene on chromosome 16 named FUS.
Somatic mutation Variants: An analysis of peripheral blood samples from 19 patients with myxoid liposarcoma linked to t(12;16) and from 1 patient with myxoid liposarcoma associated to t(12;22;20) chromosomal translocation, resulting in the fusion of the DDIT3 and EWS genes, found FUS-DDIT3 hybrid fragments in 3 patients with t(12;16) and the EWS-DDIT3 hybrid in the patient with the latter translocation.

Result of the chromosomal anomaly

Hybrid Gene
 
The FUS-CHOP fusion genes consist of the 5 promoter region and exons 1-5 or, more rarely, 1-7 or 1-8 of FUS gene fused to the complete coding region, including exons 1-4 or 2-4, of CHOP (DDIT3) gene.
Fusion Protein
Description Myxoid liposarcoma tumor developed in a FUS-DDIT3 transgenic mice (40X objetive, H-E staining).
Oncogenesis Oncogenic properties Transcriptional control of the fusion gene is dominated by the FUS housekeeping type of regulatory region, leading to stable expression of the fusion protein in tumor cells. The transforming properties of the FUS-DDIT3 fusion protein have been demonstrated in NIH 3T3 cells and fibroblasts. In the FUS-DDIT3 fusion, transcriptional activation is specifically conferred on the chimeric protein by the FUS segment after the translocation event. The portion of FUS that is present in the FUS-DDIT3 and FUS-ERG fusion proteins is similar and this part has been shown to be an autonomous transcriptional activation domain. The protein most likely functions as an abnormal transcription factor acting on a number of downstream target genes.
Mouse models In vivo, mice expressing FUS-DDIT3 develop liposarcomas. Overexpression of FUS-DDIT3 transgene driven by the elongation factor 1alpha (EF1alpha) promoter to all tissues, results in most of the symptoms of human liposarcomas, including the presence of lipoblasts with round nuclei, accumulation of intracellular lipid, induction of adipocyte-specific genes and a concordant block in the differentiation program (see figure 2). No tumours of other tissues were found in these transgenic mice despite widespread activity of the EF1alpha promoter. This establishes FUS-DDIT3 overexpression as a key determinant of human liposarcomas and provided the first in vivo evidence for a link between a fusion gene created by a chromosomal translocation and a solid tumour. In contrast, transgenic mice expressing high levels of DDIT3, which lacks the FUS domain, do not develop any tumour but consistently show the accumulation of a glycoprotein material within the terminally differentiated adipocytes, a characteristic figure of liposarcomas associated with FUS-DDIT3. However, transgenic mice expressing the altered form of DDIT3-FUS (created by the in frame fusion of the FUS domain to the carboxy end of DDIT3) developed liposarcomas. The characteristics of the liposarcomas arising in the DDIT3-FUS mice were very similar to those previously observed in the FUS-DDIT3 transgenic mice indicating that the FUS domain is required not only for transformation but also influences the phenotype of the tumor cells. These results provide evidence that the FUS domain of FUS-DDIT3 plays a specific and critical role in the pathogenesis of liposarcoma. In this sense, when mice expressing the FUS domain are crossed with DDIT3-transgenic mice to generate the double-transgenic FUSxDDIT3, these animals develop liposarcoma. These results provide genetic evidence that FUS and DDIT3 domains function in trans for the mutual restoration of liposarcoma, and identify a new mechanism of tumour-associated fusion genes which might have impact beyond myxoid liposarcoma.
  

Other genes implicated (Data extracted from papers in the Atlas)

Genes DDIT3 EWSR1 FUS LATS1

Translocations implicated (Data extracted from papers in the Atlas)

 t(12;16)(q13;p11) FUS/DDIT3
 t(12;22)(q13;q12) EWSR1/DDIT3

External links

8034 Liposarcoma, myxoid/round cell;SA lip myx
Mitelman databaseTopo ( Soft_tissue ) - Mitelman database (CGAP - NCBI)
t(12;16)(q13;p11) - Mitelman database (CGAP - NCBI)
t(12;22)(q13;q12) - Mitelman database (CGAP - NCBI)
COSMICHisto = - Site = soft_tissue (COSMIC)
arrayMapTopo ( C49) Morph ( 8858/3 LIPOSARCOMA NEOPLASMS) - arrayMap (Zurich)
Other databasecBioPortal: Sarcoma (MSKCC/Broad, Nature Genetics 2010)
Other databasecBioPortal: Sarcoma (TCGA, Provisional)

Bibliography

Cytogenetic studies of adipose tissue tumors. II. Recurrent reciprocal translocation t(12;16)(q13;p11) in myxoid liposarcomas.
Turc-Carel C, Limon J, Dal Cin P, Rao U, Karakousis C, Sandberg AA
Cancer genetics and cytogenetics. 1986 ; 23 (4) : 291-299.
PMID 3779625
 
Localization of the chromosomal breakpoints of the t(12;16) in liposarcoma to subbands 12q13.3 and 16p11.2.
Eneroth M, Mandahl N, Heim S, Willn H, Rydholm A, Alberts KA, Mitelman F
Cancer genetics and cytogenetics. 1990 ; 48 (1) : 101-107.
PMID 2372777
 
Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11).
Aman P, Ron D, Mandahl N, Fioretos T, Heim S, Arheden K, Willn H, Rydholm A, Mitelman F
Genes, chromosomes & cancer. 1992 ; 5 (4) : 278-285.
PMID 1283316
 
Isolation, characterization and chromosomal localization of the human GADD153 gene.
Park JS, Luethy JD, Wang MG, Fargnoli J, Fornace AJ Jr, McBride OW, Holbrook NJ
Gene. 1992 ; 116 (2) : 259-267.
PMID 1339368
 
CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription.
Ron D, Habener JF
Genes & development. 1992 ; 6 (3) : 439-453.
PMID 1547942
 
Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma.
Crozat A, Aman P, Mandahl N, Ron D
Nature. 1993 ; 363 (6430) : 640-644.
PMID 8510758
 
Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma.
Rabbitts TH, Forster A, Larson R, Nathan P
Nature genetics. 1993 ; 4 (2) : 175-180.
PMID 7503811
 
An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation.
Ichikawa H, Shimizu K, Hayashi Y, Ohki M
Cancer research. 1994 ; 54 (11) : 2865-2868.
PMID 8187069
 
Fusion of the FUS gene with ERG in acute myeloid leukemia with t(16;21)(p11;q22).
Panagopoulos I, Aman P, Fioretos T, Hglund M, Johansson B, Mandahl N, Heim S, Behrendtz M, Mitelman F
Genes, chromosomes & cancer. 1994 ; 11 (4) : 256-262.
PMID 7533529
 
Characterization of the CHOP breakpoints and fusion transcripts in myxoid liposarcomas with the 12;16 translocation.
Panagopoulos I, Mandahl N, Ron D, Hglund M, Nilbert M, Mertens F, Mitelman F, Aman P
Cancer research. 1994 ; 54 (24) : 6500-6503.
PMID 7987849
 
Transcriptional activation by TAL1 and FUS-CHOP proteins expressed in acute malignancies as a result of chromosomal abnormalities.
Snchez-Garca I, Rabbitts TH
Proceedings of the National Academy of Sciences of the United States of America. 1994 ; 91 (17) : 7869-7873.
PMID 8058726
 
A novel effector domain from the RNA-binding protein TLS or EWS is required for oncogenic transformation by CHOP.
Zinszner H, Albalat R, Ron D
Genes & development. 1994 ; 8 (21) : 2513-2526.
PMID 7958914
 
Chimeric TLS/FUS-CHOP gene expression and the heterogeneity of its junction in human myxoid and round cell liposarcoma.
Kuroda M, Ishida T, Horiuchi H, Kida N, Uozaki H, Takeuchi H, Tsuji K, Imamura T, Mori S, Machinami R
The American journal of pathology. 1995 ; 147 (5) : 1221-1227.
PMID 7485386
 
Two distinct FUS breakpoint clusters in myxoid liposarcoma and acute myeloid leukemia with the translocations t(12;16) and t(16;21).
Panagopoulos I, Mandahl N, Mitelman F, Aman P
Oncogene. 1995 ; 11 (6) : 1133-1137.
PMID 7566973
 
Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS.
Aman P, Panagopoulos I, Lassen C, Fioretos T, Mencinger M, Toresson H, Hglund M, Forster A, Rabbitts TH, Ron D, Mandahl N, Mitelman F
Genomics. 1996 ; 37 (1) : 1-8.
PMID 8921363
 
Genomic PCR detects tumor cells in peripheral blood from patients with myxoid liposarcoma.
Panagopoulos I, Aman P, Mertens F, Mandahl N, Rydholm A, Bauer HF, Mitelman F
Genes, chromosomes & cancer. 1996 ; 17 (2) : 102-107.
PMID 8913727
 
Identification of genes differentially expressed in TLS-CHOP carrying myxoid liposarcomas.
Thelin-Jrnum S, Lassen C, Panagopoulos I, Mandahl N, Aman P
International journal of cancer. Journal international du cancer. 1999 ; 83 (1) : 30-33.
PMID 10449603
 
Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death.
Hicks GG, Singh N, Nashabi A, Mai S, Bozek G, Klewes L, Arapovic D, White EK, Koury MJ, Oltz EM, Van Kaer L, Ruley HE
Nature genetics. 2000 ; 24 (2) : 175-179.
PMID 10655065
 
The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice.
Prez-Losada J, Pintado B, Gutirrez-Adn A, Flores T, Baares-Gonzlez B, del Campo JC, Martn-Martn JF, Battaner E, Snchez-Garca I
Oncogene. 2000 ; 19 (20) : 2413-2422.
PMID 10828883
 
Liposarcoma initiated by FUS/TLS-CHOP: the FUS/TLS domain plays a critical role in the pathogenesis of liposarcoma.
Prez-Losada J, Snchez-Martn M, Rodrguez-Garca MA, Prez-Mancera PA, Pintado B, Flores T, Battaner E, Snchez-Garia I
Oncogene. 2000 ; 19 (52) : 6015-6022.
PMID 11146553
 
Genetic characterization of angiomatoid fibrous histiocytoma identifies fusion of the FUS and ATF-1 genes induced by a chromosomal translocation involving bands 12q13 and 16p11.
Waters BL, Panagopoulos I, Allen EF
Cancer genetics and cytogenetics. 2000 ; 121 (2) : 109-116.
PMID 11063792
 
Expression of the FUS domain restores liposarcoma development in CHOP transgenic mice.
Prez-Mancera PA, Prez-Losada J, Snchez-Martn M, Rodrguez-Garca MA, Flores T, Battaner E, Gutirrez-Adn A, Pintado B, Snchez-Garca I
Oncogene. 2002 ; 21 (11) : 1679-1684.
PMID 11896599
 
Understanding mesenchymal cancer: the liposarcoma-associated t(12;16)(q13;p11) chromosomal translocation as a model.
PɬrezMancera PA
Genomics. 2002 ; 3.
 
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, Panagopoulos I
Human molecular genetics. 2003 ; 12 (18) : 2349-2358.
PMID 12915480
 
Current soft-tissue sarcoma classifications.
Daugaard S
European journal of cancer (Oxford, England : 1990). 2004 ; 40 (4) : 543-548.
PMID 14962721
 
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed

Contributor(s)

Written11-2004Manuel Sánchez-Martín, Ines González-Herrero, Isidro Sánchez-García
Laboratorio 13, Instituto de Biologia Molecular y Celular del Cancer (IBMCC), Centro de Investigacion del Cancer, Campus Unamuno, 37.007-Salamanca, Spain

Citation

This paper should be referenced as such :
Sanchez-Martin, M ; Gonzalez-Herrero, I ; Sanchez-Garcia, I
Soft tissue tumors: Liposarcoma: Myxoid liposarcoma
Atlas Genet Cytogenet Oncol Haematol. 2005;9(1):39-43.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Tumors/MyxoidLipoSarcID5169.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Sat Jul 26 14:21:26 CEST 2014


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.