Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0–86.5), 61.9% (51.6–74.2), 80.0% (95% CI 51.6–100.0), and 44.9% (95% CI 28.6–70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1–7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3–9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1–4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1–6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1–0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.

髓母细胞瘤是一种常见的儿童恶性中枢神经系统肿瘤，仅占成人脑肿瘤的一小部分。此前已有研究表明，在成人中，Sonic Hedgehog (SHH) 激活的肿瘤占主导地位，无翼型 (WNT) 和第 4 组肿瘤较少见，但分子风险分层仍然是一个挑战。我们对髓母细胞瘤高级基因组学国际联盟确定的 191 例成人髓母细胞瘤病例进​​行了综合分析，包括全基因组甲基化分析、拷贝数分析、体细胞核苷酸变异和临床变量的相关性。我们鉴定出 30 个 WNT、112 个 SHH、6 个第 3 组肿瘤和 41 个第 4 组肿瘤。与其他亚组相比，SHH 肿瘤患者在诊断时年龄明显较大 ( p  < 0.0001)。WNT、SHH、第 3 组和第 4 组肿瘤的五年无进展生存率 (PFS) 分别为 64.4 (48.0–86.5)、61.9% (51.6–74.2)、80.0% (95% CI 51.6–100.0) 和分别为 44.9% (95% CI 28.6–70.7) ( p  = 0.06)。所有临床变量（年龄、性别、转移状态、切除范围、化疗、放疗）均与亚组特异性 PFS 无关。对于 3p 染色体丢失（HR 2.9，95% CI 1.1-7.6； p  = 0.02）、10q 染色体丢失（HR 4.6，95% CI 2.3-9.4；p  < 0.0001）的病例，SHH 肿瘤患者的生存率明显较差。17p 染色体缺失（HR 2.3，95% CI 1.1–4.8；p  = 0.02）和PTCH1突变（HR 2.6，95% CI 1.1–6.2；p  = 0.04）。3p 丢失和 10q 丢失的预后意义在多变量回归模型中仍然存在。对于第 4 组肿瘤，8 号染色体丢失与生存率提高密切相关，这在非重叠队列中得到了验证（组合队列 HR 0.2，95% CI 0.1–0.7；p = 0.007 ）  。与儿科髓母细胞瘤不同，第 4 组中的整个 11 号染色体缺失和 SHH 中的 14q 号染色体缺失与生存率改善无关，其中 MYCN、GLI2 和 MYC 扩增很少见。总之，我们报告了成人髓母细胞瘤独特的亚组特异性细胞遗传学特征，这些特征与年轻患者不同，并且与生存差异相关。我们的研究结果表明，迫切需要结合针对高危成人髓母细胞瘤患者的新策略的临床试验。