突变分析揭示了复发性神经胶质瘤的起源和治疗驱动的进化。
Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma.
机构信息
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
Department ofPathology, University of California San Francisco, San Francisco, CA, USA.
出版信息
Science. 2014 Jan 10;343(6167):189-193. doi: 10.1126/science.1239947. Epub 2013 Dec 12.
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 in TP53, 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.
肿瘤复发是癌症死亡的主要原因。针对复发性疾病的治疗可能会失败，至少部分原因是驱动复发生长的基因组改变与初始肿瘤中的改变不同。为了探索这一假设，我们对 23 名接受相同治疗的低级别胶质瘤患者的初始肿瘤和复发肿瘤进行了外显子组测序。在 43%的病例中，至少有一半的初始肿瘤中的突变在复发时未被检测到，包括 TP53、ATRX、SMARCA4 和 BRAF 的驱动突变；这表明复发肿瘤通常是由初始肿瘤在其进化的早期阶段衍生的细胞播种的。值得注意的是，接受化疗药物替莫唑胺（TMZ）治疗的 10 名患者中的 6 名的肿瘤则沿着另一种进化途径发展为高级别胶质瘤。在复发时，这些肿瘤发生了超突变，并携带 RB（视网膜母细胞瘤）和 Akt-mTOR（哺乳动物雷帕霉素靶蛋白）通路的驱动突变，这些突变具有 TMZ 诱导的突变特征。
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