A Novel Type of EWS-CHOP Fusion Gene in Two Cases of Myxoid Liposarcoma

Abstract

Fusion genes consisting of TLS/FUS and CHOP or EWS and CHOP are characteristic markers for myxoid/ round cell liposarcomas (MLS/RCLS). Several different structures of the fusion genes were reported in the case of the TLS/FUS-CHOP form, whereas only one type of structure has so far been found for the EWS-CHOP form, which consisted of exons 1 to 7 of the EWS and exons 2 to 4 of the CHOP gene. Here we describe a novel type of EWS-CHOP fusion gene in two cases of MLS/RCLS, which were found in a consecutive analysis of 21 cases. This fusion gene con- Tumor-specific fusion genes resulting from reciprocal chromosomal translocations have been detected in many bone and soft tissue tumors, and are now regarded as a major factor in the development of these tumors. 1 One of the common features of the fusion genes found in sarcomas is structural diversity, which is created by two factors: the component genes themselves, one is usually common and the other variable; and genomic breakpoints or alternative splicing in the components. The diversity of fusion genes is most striking in Ewing's sarcoma. So far five different partners of the EWS gene have been reported, 2-6 and at least 12 different structures were found in the case of EWS-Fli1 fusion gene, 7,8 which is the most prevalent form of the fusion gene in Ewing's sarcoma. 8 In some tumors, the diversity seems to have biological significance, and several particular types of fusion genes were demonstrated to be associated with certain phenotypes such as prognosis or histological subtype. 8 -12 In the case of MLS/RCLS, either the TLS/FUS (hereafter simply called TLS)-CHOP or EWS-CHOP fusion gene, the result of a t(12;16)(q13;p11) or a t(12;22)(q13;q12) translocation, respectively, 13-15 was found in almost all cases 16 -18 and the two are now considered a hallmark of this type of liposarcoma. Previous data indicated that the TLS-CHOP fusion gene was far more prevalent (95 to 98%) than the EWS-CHOP gene, 16 -18 having at least nine different structures due to breakpoints or alternative splicing. 19 On the other hand, only five cases of MLS/ RCLS harboring the EWS-CHOP fusion gene have been reported in the literature, all of which shared the same structure consisting of exons 1 to 7 of the EWS gene and exons 2 to 4 of the CHOP gene (designated as the type 1 EWS-CHOP fusion gene in this report). 15,20,21 No definite correlation has been reported between any particular type of TLS-CHOP or EWS-CHOP fusion gene and the clinicopathological features of MLS/RCLS. In this report, we describe the results of fusion gene analyses of 21 cases of MLS/RCLS, in which we found a novel type of EWS-CHOP fusion gene in two cases. Materials and Methods Tumor Samples and Nucleic Acid ExtractionTwenty-one cases of MLS/RCLS were examined in this study, 13 of which were used previously in breakpoint analyses of the TLS-CHOP fusion gene. 22,23 Clinical and

Utility of FISH in the diagnosis of angiomatoid fibrous histiocytoma: a series of 18 cases

“…[6][7][8] The finding that EWSR1 (22q12) can be substituted in the place of FUS (16p11) is not surprising as EWSR1 and FUS are both members of the TET family of RNA-binding proteins; indeed, EWSR1 has been found to replace FUS as the partner of CHOP (DDIT3)(12q13) in the gene fusions of myxoid/round cell liposarcomas. 17,18 Terra et al, found by screening with FISH probes for ATF1, that 4 of 14 cases (29%) harbored rearrangements of this gene. Of these four cases, three had the EWSR1/ATF1 fusion, whereas the remaining case displayed the FUS/ATF1 fusion.…”

Multifocal Myxoid Liposarcoma—Metastasis or Second Primary Tumor?

“…At the molecular level, different breakpoints and exon combinations have been reported with different incidences (exon5-FUS/ exon3-CHOP frequency in MRLS 6%, exon8-FUS/exon2-CHOP frequency in MRLS 10%, exon7-FUS/exon2-CHOP frequency in MRLS 20%, up to 60% for exon5-FUS/ exon2-CHOP). [11][12][13][14][15][16][17] Therefore, detailed molecular analysis of breakpoints is highly suitable as a clonal marker. However, wide use is limited by the high frequency of the most common exon combinations (eg, exon5-FUS/ exon2-CHOP), resulting in an a priori chance of finding a distranslocation in two MLS cases irrespective of their clonal relation.…”

Myxoid liposarcoma with cartilaginous differentiation showing DDIT3 rearrangement

“…As MLPS with cartilaginous differentiation is a rare condition, the differential diagnosis from other benign or malignant soft tissue sarcomas, such as chondroid lipoma, extraskeletal chondroma, extraskeletal myxoid chondrosarcoma and malignant mesenchymoma, is difficult. Although chondroid lipoma and extraskeletal chondroma have cells with a similar appearance to lipoblasts (6), the presence of a plexiform capillary vascular network, is a characteristic of MLPS. Myxoid chondrosarcomas are different in that they show chondrocyte atypia (19).…”

“…This translocation leads to fusion of fused in liposarcoma (FUS; also termed translocated in liposarcoma) and DNA damage-inducible transcript 3 (DDIT3; also termed CCAAT/enhancer-binding protein homologous protein) genes, resulting in the production of the FUS-DDIT3 fusion protein (5). In another subset of MLPS, a minor chromosomal translocation, t(12;22)(q13;q12), results in fusion of the Ewing's sarcoma (EWSR1) and DDIT3 genes (6). PLPS is less frequent and harbors a complex genomic profile with numerous gains and losses similar to the genomic profile observed in poorly differentiated sarcoma (7).…”