Center for Digital Health, Berlin Institute of Health and Charité-Universitätsmedizin Berlin, Berlin, Germany.
Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Am J Pathol. 2021 Apr;191(4):602-617. doi: 10.1016/j.ajpath.2020.12.015. Epub 2021 Jan 23.
Solitary fibrous tumors (SFTs) harbor recurrent NAB2-STAT6 gene fusions, promoting constitutional up-regulation of oncogenic early growth response 1 (EGR1)-dependent gene expression. SFTs with the most common canonical NAB2 exon 4-STAT6 exon 2 fusion variant are often located in the thorax (pleuropulmonary) and are less cellular with abundant collagen. In contrast, SFTs with NAB2 exon 6-STAT6 exon 16/17 fusion variants typically display a cellular round to ovoid cell morphology and are often located in the deep soft tissue of the retroperitoneum and intra-abdominal pelvic region or in the meninges. Here, we employed next-generation sequencing-based gene expression profiling to identify significant differences in gene expression associated with anatomic localization and NAB2-STAT6 gene fusion variants. SFTs with the NAB2 exon 4-STAT6 exon 2 fusion variant showed a transcriptional signature enriched for genes involved in DNA binding, gene transcription, and nuclear localization, whereas SFTs with the NAB2 exon 6-STAT6 exon 16/17 fusion variants were enriched for genes involved in tyrosine kinase signaling, cell proliferation, and cytoplasmic localization. Specific transcription factor binding motifs were enriched among differentially expressed genes in SFTs with different fusion variants, implicating co-transcription factors in the modification of chimeric NGFI-A binding protein 2 (NAB2)-STAT6-dependent deregulation of EGR1-dependent gene expression. In summary, this study establishes a potential molecular biologic basis for clinicopathologic differences in SFTs with distinct NAB2-STAT6 gene fusion variants.
孤立性纤维瘤 (SFT) 存在反复出现的 NAB2-STAT6 基因融合，促进致癌早期生长反应 1 (EGR1) 依赖性基因表达的组成型上调。具有最常见的经典 NAB2 外显子 4-STAT6 外显子 2 融合变体的 SFT 通常位于胸部（胸膜肺），细胞较少，富含胶原。相比之下，具有 NAB2 外显子 6-STAT6 外显子 16/17 融合变体的 SFT 通常表现出圆形或卵圆形细胞形态，通常位于腹膜后深部软组织和腹腔盆腔区域或脑膜中。在这里，我们采用基于下一代测序的基因表达谱分析来确定与解剖定位和 NAB2-STAT6 基因融合变体相关的基因表达的显著差异。具有 NAB2 外显子 4-STAT6 外显子 2 融合变体的 SFT 表现出富含参与 DNA 结合、基因转录和核定位的基因的转录特征，而具有 NAB2 外显子 6-STAT6 外显子 16/17 融合变体的 SFT 则富含参与酪氨酸激酶信号转导、细胞增殖和细胞质定位的基因。在具有不同融合变体的 SFT 中，差异表达基因中富集了特定的转录因子结合基序，这表明共转录因子在修饰嵌合 NGFI-A 结合蛋白 2 (NAB2)-STAT6 依赖性 EGR1 依赖性基因表达失调中起作用。总之，这项研究为具有不同 NAB2-STAT6 基因融合变体的 SFT 的临床病理差异建立了潜在的分子生物学基础。
