Chromosomal Abnormalities in Clear Cell Sarcoma: Implications for Histogenesis

Bridge, Julia A.; Borek, Deborah; Neff, James R.; Huntrakoon, Manop

doi:10.1093/ajcp/93.1.26

Cited by 97 publications

(66 citation statements)

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“…28,29 The t(12;22) translocation fuses the EWS gene on chromosome 22 with the ATF gene on chromosome 12. 30 This translocation was first demonstrated by Bridge and co-workers 11,31 by classical cytogenetics, and subsequently confirmed by others 12-14 in shortterm and continuous cell culture lines. 32,33 To date, four separate fusion transcripts have been described in the literature.…”

Section: Discussionmentioning

confidence: 84%

“…37 Although not diagnostically helpful, polysomy of chromosome 8 is another common cytogenetic abnormality in clear cell sarcoma. 11,31 Other molecular characteristics which may have diagnostic utility in the future include activating mutations in the BRAF gene, which have been demonstrated in a significant percentage of malignant melanoma, but not clear cell sarcoma, 38 and the protein product of the epidermal growth factor receptor ERBB3 gene, which has been reported to be a marker of clear cell sarcoma. 39 A diagnostic dilemma arises when the pathologist is confronted with a malignant melanoma of unknown primary, where histologic, immunophenotypic, and clinical features resemble clear cell sarcoma.…”

Section: Discussionmentioning

confidence: 99%

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Dual-color, break-apart fluorescence in situ hybridization for EWS gene rearrangement distinguishes clear cell sarcoma of soft tissue from malignant melanoma

et al. 2005

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Clear cell sarcoma of soft tissue (malignant melanoma of soft parts) is a soft tissue sarcoma with melanocytic differentiation that typically occurs in the tendons and aponeuroses of young adults. As demonstrated by cytogenetics and reverse-transcriptase polymerase chain reaction, between 70% and over 90% of clear cell sarcomas have a t(12;22) translocation, fusing the EWS and ATF1 genes on chromosomes 22q12 and 12q13, respectively. Identification of this translocation distinguishes clear cell sarcoma from histologic mimics, most importantly conventional malignant melanoma. We report our experience with a commercially available, dualcolor, break-apart fluorescence in situ hybridization (FISH) probe, which allows detection of EWS (22q12) gene rearrangement in formalin-fixed, paraffin-embedded tissues. Histologically and immunophenotypically wellcharacterized cases of clear cell sarcoma (n ¼ 10) and malignant melanoma (n ¼ 32) were evaluated with a 22q12 dual-color, break-apart probe (Vysis, Downer's Grove, IL, USA), which spans the known common breakpoints in the EWS gene on chromosome 22 (introns 7-10). Signals from tumor cell nuclei were counted under a fluorescence microscope and the presence of red-green break-apart signals was recorded. Of the clear cell sarcoma cases, seven of 10 showed evidence of an EWS gene rearrangement with a mean of 81.6% positive cells per sample (range: 60-95%). All cases of malignant melanoma (n ¼ 32) showed virtually absent break-apart signals in the EWS gene (less than 4% cells per case). FISH detects EWS gene rearrangement in a substantial proportion of clear cell sarcomas, with excellent specificity. Importantly, EWS FISH is negative in malignant melanoma, a clinically dissimilar tumor, which may closely mimic clear cell sarcoma histologically and immunohistochemically. As the studied probe can be utilized in routinely processed tissue, FISH provides an excellent alternative to reverse-transcriptase polymerase chain reaction in cases where fresh tissue is unavailable. Modern Pathology ( Clear cell sarcoma of soft tissue (malignant melanoma of soft parts) is a rare soft tissue sarcoma with melanocytic differentiation first described by Enzinger 1 in 1965. The tumor originates predominantly in the tendons, aponeuroses, and fascial structures of the extremities of young adults. [1][2][3][4][5] Clear cell sarcoma shares morphologic, immunohistochemical, ultrastructural, and molecular features with malignant melanoma. 2,[6][7][8][9][10] In contrast to malignant melanoma, a unique and recurrent t(12;22)(q13;q12) involving the EWS gene has been identified in 70% to over 90% of clear cell sarcomas by cytogenetics, reverse-transcriptase polymerase chain reaction (RT-PCR) looking for the resultant EWS-ATF1 fusion protein, and by fluorescence in situ hybridization (FISH). [11][12][13][14][15][16][17][18][19] Clear cell sarcoma is rare and the true incidence of this neoplasm is not well established; however, the increased utilization of molecular studies for the

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Dual-color, break-apart fluorescence in situ hybridization for EWS gene rearrangement distinguishes clear cell sarcoma of soft tissue from malignant melanoma

et al. 2005

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“…Functional inhibition of p110 by bGBP results in downregulation of PI3K activity, suppression of Ras-GTP loading, consequent loss of MAPK activation and block of cell proliferation. It is of interest to notice, within the context of bGBP as a downregulator of oncogene signalling, that by mapping on human chromosome 22q12Àq13.1 (Baldini et al, 1993), a region translocated or deleted in a number of human tumours (Aurias et al, 1984;Bridge et al, 1990;Rey et al, 1993;Turc-Carel et al, 1998), the gene encoding bGBP (Chiariotti et al, 1991) is brought to attention as a prospective tumour suppressor gene.…”

Section: Inhibition Of Pi3k By Bgbp Blocks Cell Proliferation V Wellsmentioning

confidence: 99%

Functional inhibition of PI3K by the βGBP molecule suppresses Ras–MAPK signalling to block cell proliferation

2007

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The mechanisms of signal transduction from cell surface receptors to the interior of the cell are fundamental to the understanding of the role that positive and negative growth factors play in cell physiology and in human diseases. Here, we show that a functional link between phosphatidylinositol-3-OH kinase (PI3K) and Ras is suppressed by the b-galactoside binding protein (bGBP) molecule, a cytokine and a negative cell-cycle regulator. Ras-mitogen-activated protein kinase (MAPK) signalling is blocked by bGBP owing to its ability to inhibit the p110 catalytic subunit of PI3K, whose basal activity is required for Ras activation. Functional inhibition of p110 by bGBP results in downregulation of PI3K activity, suppression of Ras-GTP loading, consequent loss of MAPK activation and block of cell proliferation. This study sheds light on the molecular mechanisms whereby bGBP can control cell proliferation and, by extension, may potentially control tumorigenesis by controlling PI3K. The Ras-mitogen-activated protein kinase (MAPK) signalling pathway plays a key role in the activation dynamics of transcriptional events required for mammalian cells to enter the cell cycle. Activation of Ras requires growth factor/receptor tyrosine kinase (RTK) interaction, RTK cross-phosphorylation leading to the formation of high-affinity binding sites for SH2 domains of the Grb2 and Shc adapter proteins, the binding of the nucleotide exchange factor SOS to the SH3 domains of Grb2 and the conversion by SOS of GDP-Ras into active GTP-Ras. The ensuing signalling cascade leads to the phosphorylation of MAPK and the activation of genes programmed to initiate cell proliferation (Downward, 2003;Mitin et al., 2005 to B5 Â 10 4 receptors/cell to control cell-cycle entry and S/G 2 traverse in normal cells Mallucci, 1991, 1992). As a cytostatic factor, bGBP induces reversible S/G 2 arrest in normal cells while activating programmed cell death in cancer cells Mallucci et al, 2003). We now report that in murine embryonic fibroblasts (MEF), chosen as a paradigm of normal cells, bGBP inhibits phosphatidylinositol-3-OH kinase (PI3K) activity, also that PI3K activity is necessary for growth factor-induced activation of Ras and that basal levels are sufficient. Comparative studies with PI3K inhibitors indicate that the p110 catalytic subunit of PI3K is a prime target of bGBP-induced signalling.To determine the mode by which bGBP inhibits cell proliferation, we have investigated mechanistic events within the signalling context that lead to the phosphorylation and activation of transcription factors involved in cell-cycle entry and cell proliferation. We found (data not shown) that in MEF from secondary culture, held in G 0 by 20 nM Hu-r-bGBP and stimulated with either 10 ng/ml platelet derived growth factor (PDGF), 10 ng/ ml epidermal growth factor (EGF), 5 ng/ml fibroblast growth factor (FGF) or 10% fetal calf serum, there was no evidence of c-fos, c-jun nor, predictably, of c-myc mRNA expression indicating that no activating signals had reached the pr...

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“…Cytogenetic analysis of CCS has identified the presence of an apparently tumour-specific balanced translocation involving chromosomes 12 and 22 in more than 50% of cases (Epstein et al, 1984;Bridge et al, 1990Bridge et al, , 1991Peulvé et al, 1991;Fletcher, 1992;Reeves et al, 1992;Rodriguez et al, 1992;Speleman et al, 1992;Stenman et al, 1992;Travis and Bridge, 1992;Mrozek et al, 1993;Limon et al, 1994;Zucman et al, 1993;Nedoszytko et al, 1996;Speleman et al, 1997;Graadt van Roggen et al, 1998). This translocation results in the fusion of a portion of the Activating Transcription Factor gene (ATF-1) on the long arm of chromosome 12(12q13.1-13.2) and the Ewing's sarcoma oncogene (EWS) on chromosome 22 (22q13) (Zucman et al, 1993).…”

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confidence: 99%

Malignant melanoma is genetically distinct from clear cell sarcoma of tendons and aponeurosis (malignant melanoma of soft parts)

et al. 2001

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Summary Clear cell sarcoma of tendons and aponeuroses (malignant melanoma of soft parts) and conventional malignant melanoma may demonstrate significant morphologic overlap at the light microscopic and ultrastructural level. Consequently, the clinically relevant distinction between primary clear cell sarcoma and metastatic melanoma in the absence of a known primary cutaneous, mucosal or ocular tumour may occasionally cause diagnostic problems. A balanced translocation, t(12;22)(q13;q13), which can be detected, amongst others, using the reverse transcriptase polymerase chain reaction (RT-PCR) or fluorescent in situ hybridization (FISH), has been identified in a high percentage (50-75%) of clear cell sarcomas and is presumed to be tumour specific. Whether this chromosomal rearrangement is present in malignant melanoma has, to date, not as yet been studied by molecular genetic or molecular cytogenetic techniques. Using RT-PCR and FISH, a series of metastases from 25 known cutaneous melanomas and 8 melanoma cell lines (5 uveal and 3 cutaneous) were screened for the t(12;22)(q13;q13) translocation. Primers for RT-PCR were chosen based upon published breakpoint sequences. The Cosmids G9 and CCS2.2, corresponding to the 5′ region of EWS and 3′ region of ATF-1 respectively, were used as probes. The translocation was not identified in any of the melanomas or melanoma cell lines analysed in this study; in contrast this translocation was identified in 3 out of 5 clear cell sarcomas using these techniques. This allows distinction between translocation positive cases of clear cell sarcoma and malignant melanoma at a molecular genetic level. Consequently, in diagnostically challenging cases, this represents a valuable tool for the clinicopathologic differentiation between these two entities, with an important impact on patient management and prognosis.

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Chromosomal Abnormalities in Clear Cell Sarcoma: Implications for Histogenesis

Cited by 97 publications

References 4 publications

Dual-color, break-apart fluorescence in situ hybridization for EWS gene rearrangement distinguishes clear cell sarcoma of soft tissue from malignant melanoma

Dual-color, break-apart fluorescence in situ hybridization for EWS gene rearrangement distinguishes clear cell sarcoma of soft tissue from malignant melanoma

Functional inhibition of PI3K by the βGBP molecule suppresses Ras–MAPK signalling to block cell proliferation

Malignant melanoma is genetically distinct from clear cell sarcoma of tendons and aponeurosis (malignant melanoma of soft parts)

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