High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas
High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas
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DOI：
10.1002/gcc.20945
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发表时间：
2012-03-01
影响因子：
3.7
通讯作者：
Antonescu, Cristina R.
中科院分区：
文献类型：
--
作者：
Italiano, Antoine;Sung, Yun Shao;Antonescu, Cristina R.
儿童和年轻人的原始圆细胞肉瘤的诊断和分类一直是个问题。我们的目标是研究蓝色小圆细胞肿瘤（SBRCT）的病理和分子特征，这些肿瘤在经过详尽的免疫组化和分子筛选以排除已知的肉瘤相关易位后仍未分类。由于EWSR 1阴性的SBRCT中罕见的FUS和CIC基因重排，我们对这两个基因进行了系统的筛查。FISH检测到CIC重排15/22例（68%），而FUS无异常。RACE，RT-PCR，和/或长距离DNA PCR在两个病例中进行冷冻材料显示，CIC融合到DUX 4基因的拷贝在4 q35或10q26.3。随后的FISH分析证实了CIC与4 q35或10q26.3区域的融合信号各6例。CIC-DUX 4融合阳性肿瘤主要发生在男性年轻成年患者中（中位年龄：29岁），四肢是最常见的部位。显微镜下，肿瘤显示原始的圆形至椭圆形细胞形态，核仁突出，核分裂计数高，坏死区域。O 13表达是可变的，是弥漫性或斑片状的，肿瘤大多缺乏其他分化标志物。虽然CIC-DUX 4导致t（4;19）易位先前已在原始肉瘤中描述，但这是第一份涉及10 q26上相关DUX 4的报告。这些结果表明，一个新定义的亚组的原始圆细胞肉瘤的特点是CIC重排的可能性，不同的尤文肉瘤家族的肿瘤。(c)2011 Wiley Periodicals，Inc.
Primitive round cell sarcomas of childhood and young adults have been problematic to diagnose and classify. Our goal was to investigate the pathologic and molecular characteristics of small blue round cell tumors (SBRCT) that remained unclassified after exhaustive immunohistochemistry and molecular screening to exclude known sarcoma-related translocations. As rare examples of EWSR1-negative SBRCT have been shown to carry rearrangements for FUS and CIC genes, we undertook a systematic screening for these two genes. CIC rearrangements by FISH were detected in 15/22 (68%), while none showed FUS abnormalities. RACE, RT-PCR, and/or long-range DNA PCR performed in two cases with frozen material showed that CIC was fused to copies of the DUX4 gene on either 4q35 or 10q26.3. Subsequent FISH analysis confirmed fused signals of CIC with either 4q35 or 10q26.3 region in six cases each. Tumors positive for CIC-DUX4 fusion occurred mainly in male young adult patients (median age: 29 years), with the extremities being the most frequent location. Microscopically, tumors displayed a primitive, round to oval cell morphology with prominent nucleoli, high mitotic count, and areas of necrosis. O13 expression was variable, being either diffuse or patchy and tumors mostly lacked other markers of differentiation. Although CIC-DUX4 resulting in a t(4;19) translocation has been previously described in primitive sarcomas, this is the first report implicating the related DUX4 on 10q26 in oncogenesis. These results suggest the possibility of a newly defined subgroup of primitive round cell sarcomas characterized by CIC rearrangements, distinct from Ewing sarcoma family of tumors. (c) 2011 Wiley Periodicals, Inc.