Persistent STAG2 mutation despite multimodal therapy in recurrent pediatric glioblastoma.
Persistent STAG2 mutation despite multimodal therapy in recurrent pediatric glioblastoma.
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尽管采用多模式治疗复发性儿童胶质母细胞瘤，但 STAG2 突变仍持续存在。
DOI：
10.1038/s41525-020-0130-7
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发表时间：
2020
影响因子：
5.3
通讯作者：
Erson-Omay,EZeynep
中科院分区：
文献类型：
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作者：
Hong,ChristopherS;Vasquez,JuanC;Kundishora,AdamJ;Elsamadicy,AladineA;Beckta,JasonM;Sule,Amrita;Marks,AsherM;Leelatian,Nalin;Huttner,Anita;Bindra,RanjitS;DiLuna,MichaelL;Kahle,KristopherT;Erson-Omay,EZeynep
与成人患者类似，患有高级别胶质瘤的儿童患者的预后仍然很差。在复发时，治疗选择有限，仍然没有达成共识。这份报告描述了一名患有胶质母细胞瘤的儿童患者的基因发现，该患者接受了多次手术切除和标准化疗放射治疗，以及一种新的重组脊髓灰质炎病毒疫苗疗法。引人注目的是，尽管治疗方法多种多样，但仍有一种以有害的STAG2突变为特征的肿瘤克隆持续存在，其临床前研究中的不足可导致非整倍体和异常的有丝分裂进展，但在临床环境中仍未得到充分研究。在大体全切除、标准化疗和脊髓灰质炎病毒治疗后，突变和扩增的肿瘤克隆几乎消失，随后出现持续的STAG2突变克隆，PTPN11和BRAF罕见突变，后者由一种以前在儿童胶质母细胞瘤中未报道的新的有害突变组成(p.D594G)。伴随而来的是突变特征向DNA损伤修复缺陷增加的特征转变，这与已知的STAG2缺陷是一致的。因此，该病例代表了一份追踪aSTAG2突变的胶质母细胞瘤的临床和遗传进展的新报告，包括一种新的和新兴的免疫疗法的治疗。尽管STAG2缺乏症只包括一小部分胶质瘤，但这一病例为现有的临床前数据增加了临床证据，支持STAG2突变在胶质瘤形成和对标准治疗的耐药性中的作用。
Similar to their adult counterparts, the prognosis for pediatric patients with high-grade gliomas remains poor. At time of recurrence, treatment options are limited and remain without consensus. This report describes the genetic findings, obtained from whole-exome sequencing of a pediatric patient with glioblastoma who underwent multiple surgical resections and treatment with standard chemoradiation, as well as a novel recombinant poliovirus vaccine therapy. Strikingly, despite the variety of treatments, there was persistence of a tumor clone, characterized by a deleteriousSTAG2mutation, whose deficiency in preclinical studies can cause aneuploidy and aberrant mitotic progression, but remains understudied in the clinical setting. There was near elimination of anEGFRmutated and amplified tumor clone after gross total resection, standard chemoradiation, and poliovirus therapy, followed by the emergence of a persistentlySTAG2mutated clone, with rare mutations inPTPN11andBRAF, the latter composed of a novel deleterious mutation previously not reported in pediatric glioblastoma (p.D594G). This was accompanied by a mutation signature shift towards one characterized by increased DNA damage repair defects, consistent with the known underlyingSTAG2deficiency. As such, this case represents a novel report following the clinical and genetic progression of aSTAG2mutated glioblastoma, including treatment with a novel and emerging immunotherapy. AlthoughSTAG2deficiency comprises only a small subset of gliomas, this case adds clinical evidence to existing preclinical data supporting a role forSTAG2mutations in gliomagenesis and resistance to standard therapies.