EWSR1/FUS-CREB fusions define a distinctive malignant epithelioid neoplasm with predilection for mesothelial-lined cavities.
EWSR1/FUS-CREB fusions define a distinctive malignant epithelioid neoplasm with predilection for mesothelial-lined cavities.
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DOI：
10.1038/s41379-020-0646-5
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Antonescu CR
中科院分区：
文献类型：
--
作者：
Argani P;Harvey I;Nielsen GP;Takano A;Suurmeijer AJH;Voltaggio L;Zhang L;Sung YS;Stenzinger A;Mechtersheimer G;Dickson BC;Antonescu CR
基因融合构成关键驱动突变，通常编码异常嵌合转录因子。然而，越来越多的基因融合事件已被证明不是组织型特异性的，而是在不同的肿瘤类型之间共享的，否则在临床或表型上完全无关。染色体易位混杂的一个显著例子是EWSR1或FUS与编码creb转录因子家族（ATF1， CREB1和CREM）的基因融合，驱动跨间充质，神经外胚层和上皮谱系的各种肿瘤类型的发病机制。在这项研究中，我们研究了一组13例以前未分类的恶性上皮样肿瘤，这些肿瘤通常表现出上皮免疫表型，并明显倾向于腹腔，由EWSR1/FUS-CREB融合定义。女性7例，男性6例，平均年龄36岁（范围9 ~ 63岁）。除3例外，其余均发生在腹腔内，累及胸膜腔、上肢和下肢软组织各1例。所有肿瘤均以上皮样形态为主，伴有囊性或微囊性改变，并伴有混合或周围的可变淋巴样弯曲。除1例表达EMA和/或CK外，其余5例WT1阳性，而黑色素细胞和其他间皮瘤标志物阴性。各种RNA测序平台确认9例，FISH检测基因重排4例。11例存在crem相关融合（EWSR1-CREM， 7例；FUS-CREM， 4例），其余2例存在EWSR1-ATF1融合。临床上，7例患者出现和/或发展为转移，证实了恶性生物学潜力。我们的研究结果扩大了与creb相关融合相关的肿瘤的范围，定义了一种新的恶性上皮样肿瘤，其免疫表型提示上皮分化。该实体表现出血管瘤样纤维组织细胞瘤（囊性生长，淋巴样弯曲）和间皮瘤（累及腹膜/胸膜，上皮样表型，细胞角蛋白和WT1共表达）之间的杂交特征。
Gene fusions constitute pivotal driver mutations often encoding aberrant chimeric transcription factors. However, an increasing number of gene fusion events have been shown not to be histotype specific and shared among different tumor types, otherwise completely unrelated clinically or phenotypically. One such remarkable example of chromosomal translocation promiscuity is represented by fusions between EWSR1 or FUS with genes encoding for CREB-transcription factors family (ATF1, CREB1 and CREM), driving the pathogenesis of various tumor types spanning mesenchymal, neuroectodermal, and epithelial lineages. In this study we investigate a group of 13 previously unclassified malignant epithelioid neoplasms, frequently showing an epithelial immunophenotype and marked predilection for the peritoneal cavity, defined by EWSR1/FUS-CREB fusions. There were 7 females and 6 males, with a mean age of 36 (range 9–63). All except 3 cases occurred intra-abdominally, including one each involving the pleural cavity, upper and lower limb soft tissue. All tumors showed a predominantly epithelioid morphology associated with cystic or microcystic changes and variable lymphoid cuffing either intermixed or at the periphery. All except one case expressed EMA and/or CK, 5 were positive for WT1, while being negative for melanocytic and other mesothelioma markers. Nine cases were confirmed by various RNA sequencing platforms, while in the remaining 4 cases the gene rearrangements were detected by FISH. Eleven cases showed the presence of CREM-related fusions (EWSR1-CREM, 7; FUS-CREM, 4), while the remaining 2 harbored EWSR1-ATF1 fusion. Clinically, 7 patients presented with and/or developed metastases, confirming a malignant biologic potential. Our findings expand the spectrum of tumors associated with CREB-related fusions, defining a novel malignant epithelioid neoplasm with an immunophenotype suggesting epithelial differentiation. This entity appears to display hybrid features between angiomatoid fibrous histiocytoma (cystic growth, lymphoid cuffing) and mesothelioma (peritoneal/pleural involvement, epithelioid phenotype, and cytokeratin and WT1 co-expression).
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影响因子：
3.7
作者：
Antonescu, Cristina R.;Katabi, Nora;Weinreb, Ilan
通讯作者：
Weinreb, Ilan
影响因子：
3.7
作者：
Antonescu, Cristina R.;Dal Cin, Paola;Ladanyi, Marc
通讯作者：
Ladanyi, Marc
影响因子：
7.5
作者：
Le Loarer, Francois;Cleven, Arjen H. G.;Tirode, Franck
通讯作者：
Tirode, Franck
影响因子：
5.6
作者：
Chapman, Erin;Skalova, Alena;Ng, Tony L.
通讯作者：
Ng, Tony L.
影响因子：
5.6
作者：
Agaram, Narasimhan P.;Zhang, Lei;Antonescu, Cristina R.
通讯作者：
Antonescu, Cristina R.