Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.
JCO Precis Oncol. 2022 Aug;6:e2200048. doi: 10.1200/PO.22.00048.
Ewing sarcoma (ES) is a primitive sarcoma defined by EWSR1-ETS fusions as the primary driver alteration. To better define the landscape of cooperating secondary genetic alterations in ES, we analyzed clinical genomic profiling data of 113 patients with ES, a cohort including more adult patients (> 18 years) and more patients with advanced stage at presentation than previous genomic cohorts.
The data set consisted of patients with ES prospectively tested with the US Food and Drug Administration-cleared Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets large panel, hybrid capture-based next-generation sequencing assay. To assess the functional significance of loss, we generated ES cell lines with increased expression of and lines with knockdown of . We assessed cell viability, clonogenic growth, and motility in these ES lines and performed transcriptomic and epigenetic analyses. Finally, we validated our findings in vivo using cell line xenografts.
Novel subsets were defined by recurrent secondary alterations in , which encodes an ETS domain transcriptional repressor, in 7% of patients (five truncating mutations, one deep deletion, and two missense mutations) and in in another 2.7% (one amplification and two known activating mutations). alterations were nonoverlapping with alterations. , increased expression of decreased tumor cell growth, colony formation, and motility in two ES cell lines, whereas loss induced cellular proliferation and clonogenic growth. Transcriptomic analysis of cell lines with loss revealed an increased expression of genes and pathways associated with aggressive tumor biology, and epigenetic, chromatin-based studies revealed that competes with at ETS-binding sites.
Our findings open avenues to new insights into ES pathobiology and to novel therapeutic approaches in a subset of patients with ES.
尤因肉瘤（ES）是一种原始肉瘤，其主要驱动改变是 EWSR1-ETS 融合。为了更好地定义 ES 中合作性二次遗传改变的全景，我们分析了 113 例 ES 患者的临床基因组分析数据，该队列包括比以前的基因组队列更多的成年患者（> 18 岁）和更多处于晚期的患者。
该数据集由前瞻性接受美国食品和药物管理局批准的纪念斯隆凯特琳综合行动癌症靶点突变分析试剂盒、杂交捕获下一代测序检测的 ES 患者组成。为了评估缺失的功能意义，我们构建了 表达增加的 ES 细胞系和 敲低的细胞系。我们在这些 ES 系中评估了细胞活力、集落形成和运动能力，并进行了转录组和表观遗传学分析。最后，我们使用细胞系异种移植在体内验证了我们的发现。
在 7%的患者（五个截断突变、一个深度缺失和两个错义突变）和 中的另 2.7%（一个扩增和两个已知的激活突变）中，通过二次改变定义了新的亚组，编码 ETS 结构域转录抑制因子。 改变与 改变不重叠。 表达增加，两种 ES 细胞系的肿瘤细胞生长、集落形成和运动能力下降，而 缺失诱导细胞增殖和集落形成。 缺失细胞系的转录组分析显示，与侵袭性肿瘤生物学相关的基因和途径的表达增加，基于表观遗传学、染色质的研究表明， 与 在 ETS 结合位点竞争。
我们的研究结果为 ES 病理生物学提供了新的见解，并为 ES 患者的亚组提供了新的治疗方法。
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