Daniel Paul, Sabri Siham, Chaddad Ahmad, Meehan Brian, Jean-Claude Bertrand, Rak Janusz, Abdulkarim Bassam S
Division of Radiation Oncology, Department of Oncology, McGill University, Montréal, QC, Canada.
Department of Pathology, McGill University, Montréal, QC, Canada.
Front Oncol. 2019 Feb 4;9:41. doi: 10.3389/fonc.2019.00041. eCollection 2019.
Glioma are the most common type of malignant brain tumor, with glioblastoma (GBM) representing the most common and most lethal type of glioma. Surgical resection followed by radiotherapy and chemotherapy using the alkylating agent Temozolomide (TMZ) remain the mainstay of treatment for glioma. While this multimodal regimen is sufficient to temporarily eliminate the bulk of the tumor mass, recurrence is inevitable and often poses major challenges for clinical management due to treatment resistance and failure to respond to targeted therapies. Improved tumor profiling capacity has enabled characterization of the genomic landscape of gliomas with the overarching goal to identify clinically relevant subtypes and inform treatment decisions. Increased tumor mutational load has been shown to correlate with higher levels of neoantigens and is indicative of the potential to induce a durable response to immunotherapy. Following treatment with TMZ, a subset of glioma has been identified to recur with increased tumor mutational load. These hypermutant recurrent glioma represent a subtype of recurrence with unique molecular vulnerabilities. In this review, we will elaborate on the current knowledge regarding the evolution of hypermutation in gliomas and the potential therapeutic opportunities that arise with TMZ-induced hypermutation in gliomas.
胶质瘤是最常见的恶性脑肿瘤类型，其中胶质母细胞瘤（GBM）是最常见且最致命的胶质瘤类型。手术切除后，使用烷化剂替莫唑胺（TMZ）进行放疗和化疗仍然是胶质瘤治疗的主要手段。虽然这种多模式治疗方案足以暂时消除大部分肿瘤，但复发不可避免，而且由于治疗耐药性和对靶向治疗无反应，常常给临床管理带来重大挑战。肿瘤分析能力的提高使得能够对胶质瘤的基因组图谱进行表征，其总体目标是识别临床相关亚型并为治疗决策提供依据。肿瘤突变负荷增加已被证明与新抗原水平升高相关，表明有可能诱导对免疫治疗的持久反应。在用TMZ治疗后，已确定一部分胶质瘤复发时肿瘤突变负荷增加。这些高突变复发性胶质瘤代表了一种具有独特分子易损性的复发亚型。在本综述中，我们将详细阐述关于胶质瘤中高突变演变的现有知识，以及TMZ诱导的胶质瘤高突变所带来的潜在治疗机会。
