PDF(Pubmed)
Abstract：
Sinonasal teratocarcinosarcoma (TCS) is a rare tumor that displays a variable histology with admixtures of epithelial, mesenchymal, neuroendocrine and germ cell elements. Facing a very poor prognosis, patients with TCS are in need of new options for treatment. Recently identified recurrent mutations in SMARCA4 may serve as target for modern therapies with EZH1/2 and CDK4/6 inhibitors. Here, we present the first in vitro cell line TCS627, established from a previously untreated primary TCS originating in the ethmoid sinus with invasion into the brain. The cultured cells expressed immunohistochemical markers, indicating differentiation of epithelial, neuroepithelial, sarcomatous and teratomatous components. Whole-exome sequencing revealed 99 somatic mutations including SMARCA4, ARID2, TET2, CDKN2A, WNT7A, NOTCH3 and STAG2, all present both in the primary tumor and in the cell line. Focusing on mutated SMARCA4 as the therapeutic target, growth inhibition assays showed a strong response to the CDK4/6 inhibitor palbociclib, but much less to the EZH1/2 inhibitor valemetostat. In conclusion, cell line TCS627 carries both histologic and genetic features characteristic of TCS and is a valuable model for both basic research and preclinical testing of new therapeutic options for treatment of TCS patients.
摘要：
鼻窦畸胎癌肉瘤（TCS）是一种罕见的肿瘤，表现出可变的组织学，并伴有上皮，间充质,神经内分泌和生殖细胞元素。面对非常糟糕的预后，TCS患者需要新的治疗选择.最近发现的SMARCA4中的复发性突变可以作为EZH1/2和CDK4/6抑制剂的现代疗法的靶标。这里,我们介绍了第一个体外细胞系TCS627，它是从先前未经处理的起源于筛窦并侵入大脑的原发性TCS建立的。培养的细胞表达免疫组织化学标记，表明上皮的分化，神经上皮，肉瘤和畸胎瘤成分。全外显子组测序显示99个体细胞突变，包括SMARCA4，ARID2，TET2，CDKN2A，WNT7A,NOTCH3和STAG2均存在于原发性肿瘤和细胞系中。以突变的SMARCA4为治疗靶点，生长抑制试验显示对CDK4/6抑制剂palbociclib有强烈的反应，但更不用说EZH1/2抑制剂valemetostat了。总之,细胞系TCS627具有TCS特有的组织学和遗传特征,是治疗TCS患者的新治疗方案的基础研究和临床前测试的有价值的模型.
