We reconstructed the natural history and temporal evolution of the most common childhood brain malignancy, medulloblastoma, by single-cell whole-genome sequencing (sc-WGS) of tumours representing its major molecular sub-classes and clinical risk groups. Favourable-risk disease sub-types assessed (MB_WNT and infant desmoplastic/nodular MB_SHH) typically comprised a single clone with no evidence of further evolution. In contrast, highest risk sub-classes (MYC-amplified MB_Group3 and TP53-mutated MB_SHH) were most clonally diverse and displayed gradual evolutionary trajectories. Clinically adopted biomarkers (e.g. chromosome 6/17 aberrations; CTNNB1/TP53 mutations) were typically early-clonal/initiating events, exploitable as targets for early-disease detection; in analyses of spatially distinct tumour regions, a single biopsy was sufficient to assess their status. Importantly, sc-WGS revealed novel events which arise later and/or sub-clonally and more commonly display spatial diversity; their clinical significance and role in disease evolution post-diagnosis now require establishment. These findings reveal diverse modes of tumour initiation and evolution in the major medulloblastoma sub-classes, with pathogenic relevance and clinical potential.

我们通过对代表其主要分子亚类和临床风险组的肿瘤进行单细胞全基因组测序 (sc-WGS)，重建了最常见的儿童脑恶性肿瘤髓母细胞瘤的自然史和时间演变。评估的有利风险疾病亚型（MB _WNT和婴儿促结缔组织增生性/结节性 MB _SHH）通常包含单个克隆，没有进一步进化的证据。相比之下，风险最高的子类（MYC扩增的 MB _Group3和TP53突变的 MB _SHH）克隆多样性最高，并显示出渐进的进化轨迹。临床采用的生物标志物（例如 6/17 号染色体畸变；CTNNB1 /TP53突变）通常是早期克隆/启动事件，可用作早期疾病检测的目标；在空间不同的肿瘤区域分析中，单次活检足以评估它们的状态。重要的是，sc-WGS 揭示了后来出现的和/或亚克隆的新事件，并且更常见地显示空间多样性；现在需要确定它们的临床意义和在诊断后疾病演变中的作用。这些发现揭示了主要髓母细胞瘤亚类中肿瘤发生和演化的不同模式，具有致病相关性和临床潜力。