Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma

Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations inTP53, ATRX, SMARCA4, and BRAF; this suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis.EGA study EGAS00001000579

肿瘤复发是癌症相关死亡的首要诱因。针对复发肿瘤的治疗方案常难以奏效，究其原因至少部分在于驱动复发灶增殖的基因组变异，与原发肿瘤的基因组变异存在显著差异。为验证这一假说，本研究对23例匹配的原发性低级别胶质瘤及同一患者术后切除的复发肿瘤样本开展了外显子组测序。在43%的病例中，原发肿瘤中至少半数的突变在复发灶中未被检测到，其中包含TP53、ATRX、SMARCA4及BRAF等驱动基因的突变；这表明复发肿瘤通常起源于原发肿瘤演化早期阶段的细胞。值得注意的是，10例接受化疗药物替莫唑胺（temozolomide, TMZ）治疗的患者中，有6例的复发肿瘤通过另一套演化路径进展为高级别胶质瘤。复发时，此类肿瘤呈现高突变表型，且携带RB（视网膜母细胞瘤，retinoblastoma）与Akt-mTOR（哺乳动物雷帕霉素靶蛋白，mammalian target of rapamycin）通路的驱动基因突变，这些突变带有TMZ诱导诱变的特征。本研究隶属于欧洲基因组表型档案（European Genome-phenome Archive, EGA）收录的EGAS00001000579号研究项目。