Miller Christopher A, Dahiya Sonika, Li Tiandao, Fulton Robert S, Smyth Matthew D, Dunn Gavin P, Rubin Joshua B, Mardis Elaine R
Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Cold Spring Harb Mol Case Stud. 2018 Apr 2;4(2). doi: 10.1101/mcs.a002444. Print 2018 Apr.
As in other brain tumors, multiple recurrences after complete resection and irradiation of supratentorial ependymoma are common and frequently result in patient death. This standard-of-care treatment was established in the pregenomic era without the ability to evaluate the effect that mutagenic therapies may exert on tumor evolution and in promoting resistance, recurrence, and death. We seized a rare opportunity to characterize treatment effects and the evolution of a single patient's ependymoma across four recurrences after different therapies. A combination of high-depth whole-genome and exome-based DNA sequencing of germline and tumor specimens, RNA sequencing of tumor specimens, and advanced computational analyses were used. Treatment with radiation and chemotherapies resulted in a substantial increase in mutational burden and diversification of the tumor subclonal architecture without eradication of the founding clone. Notable somatic alterations included a driver, several epigenetic modifiers, and therapy-induced mutations that impacted multiple other cancer-relevant pathways and altered the neoantigen landscape. These genomic data provided new mechanistic insights into the genesis of ependymoma and pathways of resistance. They also revealed that radiation and chemotherapy were significant forces in shaping the increased subclonal complexity of each tumor recurrence while also failing to eradicate the founding clone. This raises the question of whether standard-of-care treatments have similar consequences in other patients with ependymoma and other types of brain tumors. If so, the perspective obtained by real-time genomic characterization of a tumor may be essential for making effective patient-specific and adaptive clinical decisions.
与其他脑肿瘤一样，幕上室管膜瘤在完全切除和放疗后多次复发很常见，且常常导致患者死亡。这种标准治疗方案是在基因组时代之前确立的，当时没有能力评估诱变疗法可能对肿瘤演变以及促进耐药性、复发和死亡产生的影响。我们抓住了一个难得的机会，对一名患者的室管膜瘤在接受不同疗法后的四次复发过程中的治疗效果和演变进行了特征分析。我们采用了对生殖系和肿瘤标本进行高深度全基因组和外显子组DNA测序、对肿瘤标本进行RNA测序以及先进的计算分析相结合的方法。放疗和化疗导致突变负担大幅增加以及肿瘤亚克隆结构多样化，但并未根除起始克隆。显著的体细胞改变包括一个驱动基因、多个表观遗传修饰因子以及影响多个其他癌症相关通路并改变新抗原格局的治疗诱导突变。这些基因组数据为室管膜瘤的发生机制和耐药途径提供了新的见解。它们还表明，放疗和化疗是塑造每次肿瘤复发时亚克隆复杂性增加的重要因素，同时也未能根除起始克隆。这就提出了一个问题，即这种标准治疗方案在其他室管膜瘤患者和其他类型脑肿瘤患者中是否会产生类似的后果。如果是这样，通过对肿瘤进行实时基因组特征分析所获得的观点对于做出有效的患者个体化和适应性临床决策可能至关重要。
