Expression of subtype-specific group 1 leiomyosarcoma markers in a wide variety of sarcomas by gene expression analysis and immunohistochemistry.
Expression of subtype-specific group 1 leiomyosarcoma markers in a wide variety of sarcomas by gene expression analysis and immunohistochemistry.
复制标题
DOI：
10.1097/pas.0b013e318211abd6
复制
发表时间：
2011-04
期刊：
影响因子：
--
通讯作者：
West RB
中科院分区：
文献类型：
--
作者：
Mills AM;Beck AH;Montgomery KD;Zhu SX;Espinosa I;Lee CH;Subramanian S;Fletcher CD;van de Rijn M;West RB
平滑肌瘤（LMS）约占所有肉瘤的四分之一，通常通过形态学标准和/或肌动蛋白或结蛋白的免疫反应性来定义。在高级别病变中，与未分化多形性肉瘤（UPS）的区别可能是有问题的，以前的研究表明，大量的LMS病例可能“隐藏”在UPS的诊断之下。我们最近描述了3种新的分子LMS亚型，它们在妇科和非妇科起源的LMS中分布相似。与其他2组相比，第1组亚型显示出疾病特异性生存期的改善，这与组织学分级无关。第1组包含所有LMS的约25%，并由基因表达的共享模式、基因组变化的独特模式以及对5种免疫组织化学（IHC）标志物（ACTG 2、CASQ 2、CFL 2、MYLK、SLMAP）中的至少3种的反应性定义，如在271例TMA中的LMS病例中所测试的。这些IHC标记物在非LMS肉瘤中尚未得到很好的表征。在这里，我们提供了这5个标志物在正常组织中的表征，另外59例LMS，以及来自44个诊断类别的565个非LMS软组织肿瘤，重点是UPS。当单独分析时，发现5个标记物在除LMS之外的许多肉瘤中表达。然而，当通过用于识别第1组LMS的相同标准进行分析时，其中当5种标志物中的至少3种反应时，病例评分为阳性，在来自仅三个诊断组的大量病例中观察到协调表达，所述诊断组包括22%的平滑肌瘤（n=22），16%的胃肠道间质瘤（n=43），子宫内膜间质肉瘤11例，占18%。此外，5%（n=57）的UPS显示出与第1组LMS相似的染色模式。为了进一步检查第1组LMS构成诊断为UPS的病例的一小部分的可能性，我们通过cDNA微阵列检查了29个UPS中来自第1组LMS表达特征的前500个基因的表达。29个UPS表达的无监督分层聚类显示，2个（7%）具有来自组1 LMS签名的基因的协调高水平表达，该速率与通过IHC分析观察到的速率相似。这些发现表明，与其他肉瘤相比，第1组LMS IHC标志物ACTG 2、CASQ 2、CFL 2、MYLK和SLMAP在协调表达时对LMS子集具有特异性，并且可能有助于识别诊断为UPS的病例中的第1组LMS病例。
Leiomyosarcomas (LMS) constitute approximately one quarter of all sarcomas and are usually defined by morphologic criteria and/or immunoreactivity for actin or desmin. Among high grade lesions, the distinction from undifferentiated pleomorphic sarcoma (UPS) can be problematic and previous studies have shown that a significant number of LMS cases may be “hiding” under the diagnosis of UPS. We recently described 3 novel molecular LMS subtypes that are distributed similarly over LMS of GYN and non-GYN origin. The Group 1 subtype shows an improved disease-specific survival compared to the other 2 groups that is independent of histologic grade. Group 1 comprises ~25% of all LMS and is defined by a shared pattern of gene expression, a distinct pattern of genomic changes, and reactivity for at least 3 of 5 immunohistochemistry (IHC) markers (ACTG2, CASQ2, CFL2, MYLK, SLMAP) as tested on 271 cases of LMS in TMAs. These IHC markers have not been well characterized in non-LMS sarcomas. Here we provide a characterization of these 5 markers across normal tissues, an additional 59 cases of LMS, and a wide range of 565 non-LMS soft tissue tumors from 44 diagnostic categories with a focus on UPS. When analyzed individually, the 5 markers were found to be expressed in many sarcomas other than LMS. However, when analyzed by the same criteria used for the recognition of Group 1 LMS where a case is scored positive when at least 3 of 5 markers reacted, coordinate expression was seen in significant numbers of cases from only three diagnostic groups that included 22% of leiomyomas (n=22), 16% of gastrointestinal stromal tumors (n=43), and 18% of endometrial stromal sarcoma (n=11). In addition, 5% (n=57) of UPS showed a staining pattern similar to that seen in Group 1 LMS. To further examine the possibility that Group 1 LMS constitutes a small part of cases diagnosed as UPS, we examined the expression of the top 500 genes from the Group 1 LMS expression signature in 29 UPS by cDNA microarray. Unsupervised hierarchical clustering of the 29 UPS expression revealed that 2 (7%) had coordinated high levels of expression of genes from the Group 1 LMS signature, a rate similar to that seen by IHC analysis. These findings show that Group 1 LMS IHC markers ACTG2, CASQ2, CFL2, MYLK, and SLMAP when coordinately expressed have specificity for a subset of LMS when compared to other sarcomas and may be useful for the recognition of Group 1 LMS cases within cases diagnosed as UPS.