Soft Tissues: Liposarcoma: Myxoid liposarcoma

2004-11-01   Manuel Sánchez-Martín , Ines González-Herrero , Isidro Sánchez-García 

Summary

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.

Class chrom clin

pour CASE-REPORT

Classification

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

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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 (fusion involved in t (12;16) in malignant liposarcoma)

Location

16p11.2

Dna rna description

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 description

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 mutations

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 (DNA damage inducible transcript 3)

Location

12q13.3

Dna rna description

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 description

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 mutations

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

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The FUS-CHOP fusion genes consist of the 5¼ 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.
Myxoid liposarcoma tumor developed in a FUS-DDIT3 transgenic mice (40X objetive, H-E staining).

Oncogenesis

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.

Bibliography

Pubmed IDLast YearTitleAuthors
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85107581993Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma.Crozat A et al
149627212004Current soft-tissue sarcoma classifications.Daugaard S et al
23727771990Localization of the chromosomal breakpoints of the t(12;16) in liposarcoma to subbands 12q13.3 and 16p11.2.Eneroth M et al
106550652000Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death.Hicks GG et al
81870691994An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation.Ichikawa H et al
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External Links

Citation

Manuel Sánchez-Martín ; Ines González-Herrero ; Isidro Sánchez-García

Soft Tissues: Liposarcoma: Myxoid liposarcoma

Atlas Genet Cytogenet Oncol Haematol. 2004-11-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/5169/soft-tissues-liposarcoma-myxoid-liposarcoma