Bulbul Ajaz, Shen John Paul, Xiu Joanne, Tamayo Pablo, Husain Hatim
, , , and , University of California San Diego, La Jolla, CA; and , Caris Life Sciences, Phoenix, AZ.
JCO Precis Oncol. 2018 Jun 1;2. doi: 10.1200/PO.17.00170. eCollection 2018.
Desmoplastic small round blue-cell tumors (DSRCTs) are sarcomas that contain the t(11;22) (p13;q12) translocation EWS-WT1 fusion protein. Because this is a rare tumor type, prospective clinical trials in DSRCT are challenging. Patients are treated in a manner similar to those with Ewing sarcoma; however, differences in prognosis and clinical presentation suggest fundamental differences in biology and potentially different therapeutic implications. This study aimed to characterize the molecular characteristics of DSRCT tumors to explore unique therapeutic options for this extremely rare and aggressive cancer type.
Thirty-five DSRCT tumors were assessed using next-generation sequencing, protein expression (immunohistochemistry), and gene amplification (chromogenic in situ hybridization or fluorescence in situ hybridization). Three patients had tumor mutational load, which was calculated as somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Gene expression data were obtained for an additional seven DSRCT tumors. Molecular alterations were compared with 88 Ewing sarcomas.
The most common alterations that distinguished DSRCTs from Ewing sarcoma included higher androgen receptor (AR), TUBB3, epidermal growth factor receptor, and TOPO2A expression. Independent analysis by RNA sequencing confirmed higher AR expression from an independent data set of EWS-WT1 fusion-positive DSRCTs compared with Ewing sarcoma and a pan-cancer analysis. DSRCTs had somatic mutations that were identified in and , averaged five mutations per megabase, and no programmed death-ligand 1 expression was detected in any DSRCT samples.
The current analysis provides the first comparative analysis, to our knowledge, of molecular aberrations that distinguish DSRCT from Ewing sarcoma. High AR expression seems to be a defining event in these malignancies, and additional investigation of the responsiveness of AR inhibitors in this disease is encouraged.
促纤维组织增生性小圆细胞肿瘤（DSRCT）是一种肉瘤，其包含t(11;22)(p13;q12)易位的EWS-WT1融合蛋白。由于这是一种罕见的肿瘤类型，DSRCT的前瞻性临床试验具有挑战性。患者的治疗方式与尤因肉瘤患者相似；然而，预后和临床表现的差异表明其生物学存在根本差异，并可能具有不同的治疗意义。本研究旨在表征DSRCT肿瘤的分子特征，以探索针对这种极其罕见且侵袭性癌症类型的独特治疗选择。
使用下一代测序、蛋白表达（免疫组织化学）和基因扩增（显色原位杂交或荧光原位杂交）对35个DSRCT肿瘤进行评估。3例患者有肿瘤突变负荷，其计算为用592基因panel测序的体细胞非同义错义突变。另外7个DSRCT肿瘤获得了基因表达数据。将分子改变与88个尤因肉瘤进行比较。
将DSRCT与尤因肉瘤区分开来的最常见改变包括更高的雄激素受体（AR）、TUBB3、表皮生长因子受体和TOPO2A表达。通过RNA测序的独立分析证实，与尤因肉瘤和泛癌分析相比，来自EWS-WT1融合阳性DSRCT独立数据集的AR表达更高。DSRCT有体细胞突变，在[具体内容缺失]和[具体内容缺失]中被鉴定，平均每兆碱基有5个突变，并且在任何DSRCT样本中均未检测到程序性死亡配体1表达。
据我们所知，当前分析首次提供了区分DSRCT与尤因肉瘤的分子畸变的比较分析。高AR表达似乎是这些恶性肿瘤中的决定性事件，鼓励对AR抑制剂在该疾病中的反应性进行进一步研究。
