Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
Cancer Res. 2019 May 1;79(9):2111-2123. doi: 10.1158/0008-5472.CAN-18-3441. Epub 2019 Mar 15.
Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. To understand the mechanisms of tumor evolution in this cancer, we performed whole-genome sequencing with linked reads on longitudinally resected pGBM samples. Our analyses showed that all diagnostic and recurrent samples were collections of genetically diverse subclones. Clonal composition rapidly evolved at recurrence, with less than 8% of nonsynonymous single-nucleotide variants being shared in diagnostic-recurrent pairs. To track the origins of the mutational events observed in pGBM, we generated whole-genome datasets for two patients and their parents. These trios showed that genetic variants could be (i) somatic, (ii) inherited from a healthy parent, or (iii) in the germlines of pGBM patients. Analysis of variant allele frequencies supported a model of tumor growth involving slow-cycling cancer stem cells that give rise to fast-proliferating progenitor-like cells and to nondividing cells. Interestingly, radiation and antimitotic chemotherapeutics did not increase overall tumor burden upon recurrence. These findings support an important role for slow-cycling stem cell populations in contributing to recurrences, because slow-cycling cell populations are expected to be less prone to genotoxic stress induced by these treatments and therefore would accumulate few mutations. Our results highlight the need for new targeted treatments that account for the complex functional hierarchies and genomic heterogeneity of pGBM. SIGNIFICANCE: This work challenges several assumptions regarding the genetic organization of pediatric GBM and highlights mutagenic programs that start during early prenatal development. http://cancerres.aacrjournals.org/content/canres/79/9/2111/F1.large.jpg.
小儿脑胶质瘤（pGBM）是一种致命的癌症，目前尚无有效的治疗方法。为了了解这种癌症中肿瘤进化的机制，我们对经纵向切除的 pGBM 样本进行了全基因组测序和链接读取分析。我们的分析表明，所有的诊断和复发样本都是遗传上多样化的亚克隆的集合。在复发时，克隆组成迅速进化，诊断-复发对中仅有不到 8%的非同义单核苷酸变异是共享的。为了追踪在 pGBM 中观察到的突变事件的起源，我们为两名患者及其父母生成了全基因组数据集。这三个患者家庭表明，遗传变异可以是（i）体细胞的，（ii）来自健康父母的遗传，或（iii）pGBM 患者的种系中的遗传。变异等位基因频率的分析支持一种肿瘤生长模型，涉及到缓慢循环的肿瘤干细胞，这些细胞会产生快速增殖的祖细胞样细胞和非分裂细胞。有趣的是，在复发时，辐射和抗有丝分裂化疗并没有增加总体肿瘤负担。这些发现支持了慢循环肿瘤干细胞群体在导致复发中的重要作用，因为这些治疗方法预计会使慢循环细胞群体较少受到遗传毒性应激的影响，因此积累的突变较少。我们的研究结果强调了需要新的靶向治疗方法，以考虑到 pGBM 的复杂功能层次结构和基因组异质性。
