Detection of myxoid liposarcoma-associated FUS–DDIT3 rearrangement variants including a newly identified breakpoint using an optimized RT-PCR assay

Powers, Maureen A.; Wang, Wei Lien; Hernandez, Vivian S.; Patel, Kayuri U.; Lev, Dina; Lazar, Alexander J.; López‐Terrada, Dolores

doi:10.1038/modpathol.2010.118

Cited by 69 publications

(43 citation statements)

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“…But MLS is distinguished from DFML by the lower extremities fascial planes predilection, the infiltration of surrounding structures, and the presence of lipoblasts on higher magnification [1,9]. Furthermore, molecular studies had shown that MLS was characterized by the recurrent translocations t(12;16)(q13;p11) and, less commonly, t(12;22)(q13;q12), which fuse FUS or EWSR1, respectively, to DDIT3 on chromosome 12 gene [10]. Narendra et al confirmed that FISH with DDIT 3 break-apart probe was a valuable adjunct in diagnosis or differential diagnosis of MLS [11].…”

Section: Discussionmentioning

confidence: 99%

Dendritic fibromyxolipoma in the right inguinal and perineum regions: a case report and review of the literature

et al. 2013

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A 32-year-old woman presented with a slow-growing, painless, subcutaneous lesion in the right inguinal and perineum regions. The mass was 24.0 cm × 10.5 cm × 5.0 cm in size, well circumscribed, mobile, and rubbery. Microscopically, the resected mass was mainly composed by a proliferation of small spindle or stellate cells, variably admixed with mature adipose tissue, embedded within an abundant myxoid and collagenized stroma. Immunohistochemically, the spindle and stellate cells were strongly positive for vimentin, CD34, and bcl-2 antibodies but not for smooth muscle actin and desmin. The tumor was diagnosed as dendritic fibromyxolipoma based on the typical findings of histology and immunohistochemistry. Clinical follow-up of 9 months after surgery revealed no evidence of recurrence. We report the first case of dendritic fibromyxolipoma in the right inguinal and perineum regions and discuss the different diagnosis.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1313680868103019.

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Section: Discussionmentioning

confidence: 99%

Dendritic fibromyxolipoma in the right inguinal and perineum regions: a case report and review of the literature

et al. 2013

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“…5 Myxoid liposarcoma represents 20-30% of all liposarcomas, mostly occurs in young adults, and is characterized by a translocation t(12;16)(q13;p11) or, in a few percent of the cases, a t(12;22)(q13;q12), leading to the chimeric fusion product FUS-DDIT3 or EWSR1-DDIT3, respectively. 25,26 According to the literature, one-third of myxoid liposarcoma patients develop distant metastases, 18,27,28 so effective systemic therapy is needed to improve the prognosis of many patients. Previous studies reported NY-ESO-1 expression in 95-100% of myxoid liposarcomas; these results were based on sample sizes ranging from 25 to 38 cases.…”

Section: Ny-eso-1 In Mesenchymal Tumorsmentioning

confidence: 99%

NY-ESO-1 (CTAG1B) expression in mesenchymal tumors

et al. 2015

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New York esophageal squamous cell carcinoma 1 (NY-ESO-1, CTAG1B) is a cancer-testis antigen and currently a focus of several targeted immunotherapeutic strategies. We performed a large-scale immunohistochemical expression study of NY-ESO-1 using tissue microarrays of mesenchymal tumors from three institutions in an international collaboration. A total of 1132 intermediate and malignant and 175 benign mesenchymal lesions were enrolled in this study. Immunohistochemical staining was performed on tissue microarrays using a monoclonal antibody for NY-ESO-1. Among mesenchymal tumors, myxoid liposarcomas showed the highest positivity for NY-ESO-1 (88%), followed by synovial sarcomas (49%), myxofibrosarcomas (35%), and conventional chondrosarcomas (28%). Positivity of NY-ESO-1 in the remaining mesenchymal tumors was consistently low, and no immunoreactivity was observed in benign mesenchymal lesions. On the basis of these findings, nearly 90% of myxoid liposarcomas, as well as a significant proportion of synovial sarcomas, myxofibrosarcomas, and conventional chondrosarcomas are good candidates for immunotherapy targeting NY-ESO-1. Modern Pathology (2015) 28, 587-595; doi:10.1038/modpathol.2014.155; published online 21 November 2014New York esophageal squamous cell carcinoma 1 (NY-ESO-1), encoded by the CTAG1B gene, is a cancer-testis antigen that was identified in 1997 from the serum of a patient with esophageal squamous cell carcinoma. 1 Cancer-testis antigens such as NY-ESO-1 have attracted increasing attention as immunotherapeutic targets because, among normal tissues, they are expressed only in adult testis germ cells and are atypically re-expressed in many malignancies. 2,3 NY-ESO-1 is of particular interest to researchers and clinicians because it is highly immunogenic and is expressed in a variety of carcinomas, melanomas, and sarcomas. 4 A recent clinical trial of adoptive immunotherapy, using genetically modified T cells directed against NY-ESO-1, demonstrated objective clinical responses in a number of metastatic synovial sarcoma and melanoma patients with NY-ESO-1-positive tumors. 5 The results of that clinical trial highlight the potential effectiveness of immunotherapy against tumors expressing NY-ESO-1, and several clinical trials (using antigen sensitization, adoptive T-cell transfer, and dendritic cell vaccine strategies) are currently underway.Mesenchymal tumors arising from bone or soft tissues comprise many histologic subtypes, which even when taken together occur at a much lower rate than the more common carcinomas, creating a practical barrier to developing new drug therapies. However, the well-defined biology of many sarcomas suggests they may be particularly susceptible to appropriate targeted strategies. Recent studies have reported NY-ESO-1 expression in an especially large proportion of myxoid liposarcomas and synovial sarcomas. 2,6-9 These studies also revealed the

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“…13;14 At least eleven different FUS-DDIT3 fusion types have been described and the fusion type does not impact clinical outcome. 2;13;15 Less than 5% of the cases harbour a t(12;22)(q13;q12) leading to an EWSR1-DDIT3 fusion, of which four different transcripts are described. 1;15;16 …”

Section: Introductionmentioning

confidence: 99%

Establishment and characterization of a new human myxoid liposarcoma cell line (DL-221) with the FUS-DDIT3 translocation

Graaff

Beird

et al. 2016

Laboratory Investigation

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Myxoid liposarcoma has the pathognomonic fusion oncogene FUS-DDIT3 encoding a chimeric transcription factor. Metastatic risk is higher with an increased round cell component and has been linked to aberrations involving the IGFR/PI3K/AKT pathway. These molecular insights have yet to translate to targeted therapies and the lack of experimental models is a major hindrance. We describe the initial in-depth characterization of a new cell line (DL-221) and establishment of a mouse xenograft model. The cell line DL-221 was derived from a metastatic pleural lesion showing myxoid and round cell histology. This newly established cell line was characterized for phenotypic properties and molecular cytogenetic profile, using PCR, COBRA-FISH and western blot. Next-generation whole exome sequencing was performed to further characterize the cell line and the parent tumor. NOD-SCID-IL2R gamma knockout mice were xenograft hosts. DL-221 cells grew an adhering monolayer and COBRA-FISH showed an aneuploid karyotype with t(12;16)(q13;p11) and several other rearrangements; RT-PCR demonstrated a FUS-DDIT3 fusion transcript type 1. Both the cell line and the original tumor harbored a TP53 compound heterozygous mutation in exon 4 and 7 and were wild type for PIK3CA. Moreover, among the 1254 variants called by whole exome sequencing, there was 77% concordance between the cell line and parent tumor. The recently described hotspot mutation in the TERT promoter region in myxoid liposarcomas was also found at C228T in DL-221. Xenografts suitable for additional pre-clinical studies were successfully established in mice after subcutaneous injection. The established DL-221 cell line is the only published available myxoid liposarcoma cell line that underwent spontaneous immortalization, without requiring SV40 transformation. The cell line and its xenograft model are unique and helpful tools to study the biology and novel potential targeted treatment approaches for myxoid liposarcoma.

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Detection of myxoid liposarcoma-associated FUS–DDIT3 rearrangement variants including a newly identified breakpoint using an optimized RT-PCR assay

Cited by 69 publications

References 20 publications

Dendritic fibromyxolipoma in the right inguinal and perineum regions: a case report and review of the literature

Dendritic fibromyxolipoma in the right inguinal and perineum regions: a case report and review of the literature

NY-ESO-1 (CTAG1B) expression in mesenchymal tumors

Establishment and characterization of a new human myxoid liposarcoma cell line (DL-221) with the FUS-DDIT3 translocation

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