MYC/MYCN 是髓母细胞瘤 (MB) 中最常见的癌基因扩增及其高危 (HR) 疾病的主要生物标志物。然而，虽然许多患者的 MYC(N) 扩增肿瘤难以治疗，但有些患者实现了长期生存。因此，我们研究了 MYC(N) 扩增 MB 内的临床生物学异质性，并确定其与改善疾病管理的相关性。我们描述了 MYC-（MYC-MB；n = 64）和 MYCN 扩增 MB（MYCN-MB）的临床和分子相关性。 ；n = 95)，来自 >1600 个诊断病例。大多数 MYC-MB 为分子组 3（46/58；79% 可评估），诊断时年龄≥3 岁（44/64 [69%]）。我们确定了一个“典型的”极高风险 (VHR) MYC 扩增组 (n = 51/62; 82%)，无论治疗如何，其生存率都很低（5 年无进展生存率 [PFS] 为 11%），定义为与 ≥1 个额外确定的危险因素（次全手术切除 [STR]、转移性疾病、LCA 病理）同时发生，并且通常为具有高比例扩增细胞的组 3/4 亚组 2。大多数剩余的非典型 MYC-MB 存活下来（即非组 3/没有其他风险特征的组 3；11/62 (18%)；5 年 PFS 为 61%）。 MYCN存活率主要与分子组相关； MYCN 扩增的 SHH MB 和具有额外危险因素的 3/4 MB 组，分别定义了 VHR 和 HR 组（VHR，39% [35/89]；20% 5 年 PFS/HR，33% [29/89] ; 5 年 PFS 为 46%）。 35 个可评估的 MYCN 扩增的 SHH 肿瘤中有 22 个含有 TP53 突变； 9/12 (75%) 的数据是种系的。没有其他危险因素的 MYCN 扩增组 3/4 MB (28%；25/89) 的 5 年 PFS 率为 70%。MYC(N) 扩增的 MB 显示出显着的临床生物学异质性。结合分子组、亚组和临床因素的诊断有助于进行风险评估。 VHR“典型”MYC 肿瘤本质上是无法治愈的，而 SHH-MYCN 扩增的 MB 的情况极差（5 年生存率为 20%）；两者都需要紧急制定替代治疗策略。传统的风险适应疗法适合反应性更强的群体，例如非典型 MYC 和非 SHH-MYCN MB。© 作者 2024。由牛津大学出版社代表神经肿瘤学会出版。

MYC/MYCN are the most frequent oncogene amplifications in medulloblastoma (MB) and its primary biomarkers of high-risk (HR) disease. However, while many patients' MYC(N)-amplified tumors are treatment-refractory, some achieve long-term survival. We therefore investigated clinicobiological heterogeneity within MYC(N)-amplified MB and determined its relevance for improved disease management.We characterized the clinical and molecular correlates of MYC- (MYC-MB; n = 64) and MYCN-amplified MBs (MYCN-MB; n = 95), drawn from >1600 diagnostic cases.Most MYC-MBs were molecular group 3 (46/58; 79% assessable) and aged ≥3 years at diagnosis (44/64 [69%]). We identified a "canonical" very high-risk (VHR) MYC-amplified group (n = 51/62; 82%) with dismal survival irrespective of treatment (11% 5-year progression-free survival [PFS]), defined by co-occurrence with ≥1 additional established risk factor(s) (subtotal surgical-resection [STR], metastatic disease, LCA pathology), and commonly group 3/4 subgroup 2 with a high proportion of amplified cells. The majority of remaining noncanonical MYC-MBs survived (i.e. non-group 3/group 3 without other risk features; 11/62 (18%); 61% 5-year PFS). MYCN survival was primarily related to molecular group; MYCN-amplified SHH MB, and group 3/4 MB with additional risk factors, respectively defined VHR and HR groups (VHR, 39% [35/89]; 20% 5-year PFS/HR, 33% [29/89]; 46% 5-year PFS). Twenty-two out of 35 assessable MYCN-amplified SHH tumors harbored TP53 mutations; 9/12 (75%) with data were germline. MYCN-amplified group 3/4 MB with no other risk factors (28%; 25/89) had 70% 5-year PFS.MYC(N)-amplified MB displays significant clinicobiological heterogeneity. Diagnostics incorporating molecular groups, subgroups, and clinical factors enable their risk assessment. VHR "canonical" MYC tumors are essentially incurable and SHH-MYCN-amplified MBs fare extremely poorly (20% survival at 5 years); both require urgent development of alternative treatment strategies. Conventional risk-adapted therapies are appropriate for more responsive groups, such as noncanonical MYC and non-SHH-MYCN MB.© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.