Undifferentiated pleomorphic sarcoma (UPS) is a highly aggressive soft tissue tumor. A subset of UPS is characterized by a CITED2-PRDM10 or a MED12-PRDM10 gene fusion. Preliminary data suggest that these so-called PRDM10-rearranged tumors (PRT) are clinically more indolent than classical high-grade UPS, and hence important to recognize. Here, we assessed the spectrum of accompanying mutations and the gene expression profile in PRT using genomic arrays and sequencing of the genome (WGS) and transcriptome (RNA-seq). The fusion protein's function was further investigated by conditional expression of the CITED2-PRDM10 fusion in a fibroblast cell line, followed by RNA-seq and an assay for transposase-accessible chromatin (ATAC-seq). The CADM3 gene was found to be differentially up-regulated in PRT and cell lines and was also evaluated for expression at the protein level using immunohistochemistry (IHC). The genomic analyses identified few and nonrecurrent mutations in addition to the structural variants giving rise to the gene fusions, strongly indicating that the PRDM10-fusions represent the critical driver mutations. RNA-seq of tumors showed a distinct gene expression profile, separating PRT from high-grade UPS and other soft tissue tumors. CADM3 was among the genes that was consistently and highly expressed in both PRT and fibroblasts expressing CITED2-PRDM10, suggesting that it is a direct target of the PRDM10 transcription factor. This conclusion is in line with sequencing data from ATAC-seq, showing enrichment of PRDM10 binding sites, suggesting that the amino-terminal fusion partner contributes by making the DNA more accessible to PRDM10 binding. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

中文翻译：

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具有 PRDM10 融合的未分化多形性肉瘤具有独特的基因表达谱。


未分化多形性肉瘤（UPS）是一种高度侵袭性的软组织肿瘤。 UPS 的一个子集以 CITED2-PRDM10 或 MED12-PRDM10 基因融合为特征。初步数据表明，这些所谓的 PRDM10 重排肿瘤 (PRT) 在临床上比经典的高级别 UPS 更惰性，因此认识到这一点很重要。在这里，我们使用基因组阵列以及基因组测序 (WGS) 和转录组 (RNA-seq) 评估了 PRT 中伴随突变的谱和基因表达谱。通过在成纤维细胞系中条件表达 CITED2-PRDM10 融合体，然后进行 RNA-seq 和转座酶可及染色质 (ATAC-seq) 测定，进一步研究了融合蛋白的功能。发现 CADM3 基因在 PRT 和细胞系中差异上调，并且还使用免疫组织化学 (IHC) 评估了蛋白质水平的表达。除了引起基因融合的结构变异之外，基因组分析还发现了很少的非复发突变，这强烈表明 PRDM10 融合代表了关键的驱动突变。肿瘤的 RNA 测序显示出独特的基因表达谱，将 PRT 与高级 UPS 和其他软组织肿瘤区分开来。 CADM3 是在 PRT 和表达 CITED2-PRDM10 的成纤维细胞中一致且高表达的基因之一，表明它是 PRDM10 转录因子的直接靶标。这一结论与 ATAC-seq 的测序数据一致，显示了 PRDM10 结合位点的富集，表明氨基末端融合伴侣通过使 DNA 更容易与 PRDM10 结合而发挥作用。 © 2019 大不列颠及爱尔兰病理学会。由约翰·威利父子有限公司出版