EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma.

The molecular hallmark of angiomatoid fibrous histiocytoma (AFH) is not well defined, with only six cases with specific gene fusions reported to date, consisting of either FUS-ATF1 or EWSR1-ATF1. To address this, we investigated the presence of FUS-ATF1, EWSR1-ATF1, and the highly related EWSR1-CREB1 fusion in a group of nine AFHs. All cases were subjected to RT-PCR for EWSR1-ATF1 and EWSR1-CREB1. FISH for EWSR1 and FUS rearrangements was performed in most cases. Transcriptional profiling was performed in three tumors and their gene expression was compared to five clear cell sarcomas expressing either the EWSR1-ATF1 or EWSR1-CREB1 fusion. By RT-PCR, eight out of nine tumors showed the presence of the EWSR1-CREB1 fusion, while one had an EWSR1-ATF1 transcript. FISH showed evidence of EWSR1 rearrangement in seven out of eight cases. Karyotypic analysis performed in one tumor showed a t(2;22)(q33;q12). High transcript levels were noted for TFE3 in AFH tumors, while overexpression of genes involved in melanogenesis, such as MITF, GP100, and MET was noted in somatic clear cell sarcomas. We report for the first time the presence of EWSR1-CREB1 in AFH, which now appears to be the most frequent gene fusion in this tumor. EWSR1-CREB1 is a novel translocation recently described in clear cell sarcoma of the GI tract. EWSR1-ATF1, identified in some AFH cases, is the most common genetic abnormality in soft tissue clear cell sarcoma. Thus, identical fusions involving ATF1 and CREB1 are found in two distinct sarcomas, which may be able to transform two different types of mesenchymal precursor cells, unlike most other sarcoma gene fusions.

Antonescu CR ，Dal Cin P ，Nafa K ，Teot LA ，Surti U ，Fletcher CD ，Ladanyi M ... -  《GENES CHROMOSOMES & CANCER》

EWSR1-CREB1 and EWSR1-ATF1 fusion genes in angiomatoid fibrous histiocytoma.

Rossi S ，Szuhai K ，Ijszenga M ，Tanke HJ ，Zanatta L ，Sciot R ，Fletcher CD ，Dei Tos AP ，Hogendoorn PC ... -  《CLINICAL CANCER RESEARCH》

Endobronchial pulmonary angiomatoid fibrous histiocytoma: two cases with EWSR1-CREB1 and EWSR1-ATF1 fusions.

Thway K ，Nicholson AG ，Wallace WA ，Al-Nafussi A ，Pilling J ，Fisher C ... -  《-》

Angiomatoid fibrous histiocytoma: comparison of fluorescence in situ hybridization and reverse transcription polymerase chain reaction as adjunct diagnostic modalities.

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm of intermediate biologic potential and uncertain differentiation, most often arising in the extremities of children and young adults. Although it has characteristic histologic features of a lymphoid cuff surrounding nodules of ovoid cells with blood-filled cystic cavities, diagnosis is often difficult due to its morphologic heterogeneity and lack of specific immunoprofile. Angiomatoid fibrous histiocytoma is associated with recurrent chromosomal translocations, leading to characteristic EWSR1-CREB1, EWSR1-ATF1, and, rarely, FUS-ATF1 gene fusions; fluorescence in situ hybridization (FISH), detecting EWSR1 or FUS rearrangements, and reverse transcription-polymerase chain reaction (RT-PCR) for EWSR1-CREB1 and EWSR1-ATF1 fusion transcripts have become routine ancillary tools. We present a large comparative series of FISH and RT-PCR for AFH. Seventeen neoplasms (from 16 patients) histologically diagnosed as AFH were assessed for EWSR1 rearrangements or EWSR1-CREB1 and EWSR1-ATF1 fusion transcripts. All 17 were positive for either FISH or RT-PCR or both. Of 16, 14 (87.5%) had detectable EWSR1-CREB1 or EWSR1-ATF1 fusion transcripts by RT-PCR, whereas 13 (76.5%) of 17 had positive EWSR1 rearrangement with FISH. All 13 of 13 non-AFH control neoplasms failed to show EWSR1-CREB1 or EWSR1-ATF1 fusion transcripts, whereas EWSR1 rearrangement was present in 2 of these 13 cases (which were histopathologically myoepithelial neoplasms). This study shows that EWSR1-CREB1 or EWSR1-ATF1 fusions predominate in AFH (supporting previous reports that FUS rearrangement is rare in AFH) and that RT-PCR has a comparable detection rate to FISH for AFH. Importantly, cases of AFH can be missed if RT-PCR is not performed in conjunction with FISH, and RT-PCR has the added advantage of specificity, which is crucial, as EWSR1 rearrangements are present in a variety of neoplasms in the histologic differential diagnosis of AFH, that differ in behavior and treatment.

Thway K ，Gonzalez D ，Wren D ，Dainton M ，Swansbury J ，Fisher C ... -  《-》

Clear cell sarcoma of soft tissue: a clinicopathologic, immunohistochemical, and molecular analysis of 33 cases.

Hisaoka M ，Ishida T ，Kuo TT ，Matsuyama A ，Imamura T ，Nishida K ，Kuroda H ，Inayama Y ，Oshiro H ，Kobayashi H ，Nakajima T ，Fukuda T ，Ae K ，Hashimoto H ... -  《AMERICAN JOURNAL OF SURGICAL PATHOLOGY》