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Solitary fibrous tumors: loss of chimeric protein expression and genomic instability mark dedifferentiation.

孤立性纤维性肿瘤:嵌合蛋白表达缺失及基因组不稳定性是去分化的标记

Dagrada GP,Spagnuolo RD,Mauro V,Tamborini E,Cesana L,Gronchi A,Stacchiotti S,Pierotti MA,Negri T,Pilotti S

Abstract

Solitary fibrous tumors, which are characterized by their broad morphological spectrum and unpredictable behavior, are rare mesenchymal neoplasias that are currently divided into three main variants that have the NAB2-STAT6 gene fusion as their unifying molecular lesion: usual, malignant and dedifferentiated solitary fibrous tumors. The aims of this study were to validate molecular and immunohistochemical/biochemical approaches to diagnose the range of solitary fibrous tumors by focusing on the dedifferentiated variant, and to reveal the genetic events associated with dedifferentiation by integrating the findings of array comparative genomic hybridization. We studied 29 usual, malignant and dedifferentiated solitary fibrous tumors from 24 patients (including paired samples from five patients whose tumors progressed to the dedifferentiated form) by means of STAT6 immunohistochemistry and (when frozen material was available) reverse-transcriptase polymerase chain reaction and biochemistry. In addition, the array comparative genomic hybridization findings were used to profile 12 tumors from nine patients. The NAB2/STAT6 fusion was detected in all of the tumors, but immunohistochemistry and western blotting indicated that chimeric protein expression was atypical or absent in 9 out of 11 dedifferentiated tumors. The comparative genomic hybridization results revealed that the usual and malignant solitary fibrous tumors had a simple profile, whereas the genome of the dedifferentiated tumors was complex and unstable, and suggested that 13q and 17p deletions and TP53 mutations may be present in malignant lesions before the full expression of a dedifferentiated phenotype. Solitary fibrous tumor dedifferentiation is associated with the loss of chimeric oncoprotein expression, genomic instability, and cell decommitment and reprogramming. The assessment of dedifferentiated solitary fibrous tumors is based on the presence of the fusion transcripts and, in principle, negative STAT6 immunohistochemistry should not rule out a diagnosis of solitary fibrous tumor.

摘要

孤立性纤维性肿瘤,是罕见的间叶性肿瘤,其特点是形态学谱系广、生物学行为不可预知,目前分为三个主要亚型:普通型、恶性和去分化孤立性纤维性肿瘤,三者有共同的分子改变即NAB2-STAT6融合基因。

本研究的目的是证实利用分子和免疫组化/生化方法可以诊断孤立性纤维性肿瘤各亚型,重点是去分化亚型,并通过整合阵列比较基因组杂交结果揭示与肿瘤去分化相关的基因改变。我们通过STAT6免疫组化方法、(可获得冰冻组织时)RT-PCR方法和生物化学方法研究了24位患者29例普通型、恶性和去分化孤立性纤维性肿瘤(包括来自五例患者进展为去分化肿瘤的配对样本)。此外,9位患者12例肿瘤利用阵列比较基因组杂交的结果明确基因改变。所有肿瘤均检测出NAB2/STAT6融合,但免疫组化和Western印迹显示9/11例去分化肿瘤嵌合蛋白表达不典型或缺失。

比较基因组杂交结果显示,普通型和恶性孤立性纤维性肿瘤有单一基因型,而去分化肿瘤基因型常常是复杂和不稳定的,并提示13q和17p的缺失及TP53基因突变可能在去分化表型充分展现前在恶性病变中存在。孤立性纤维性肿瘤去分化与嵌合癌蛋白表达缺失、基因组不稳定和细胞谱系性紊乱和重编码相关。去分化孤立性纤维性肿瘤的评估是基于融合转录因子的存在,原则上,免疫组化STAT6阴性不应排除孤立性纤维性肿瘤的诊断。

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