Department of Neurosurgery, New York Medical College/Westchester Medical Center, Valhalla, NY, U.S.A.
Anticancer Res. 2022 May;42(5):2225-2239. doi: 10.21873/anticanres.15703.
Medulloblastoma (MB) is the most common malignant pediatric posterior fossa tumor. Recent genetic, epigenetic, and transcriptomic analyses have classified MB into three subgroups, Wingless Type (WNT), Sonic Hedgehog (SHH), and non-WNT/non-SHH (originally termed Group 3 and Group 4), with discrete patient profiles and prognoses. WNT is the least common subgroup with the best prognosis, characterized by nuclear β-catenin expression, mutations in Catenin beta-1 (CTNNB1), and chromosome 6 monosomy. SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway. Originally, the presence of TP53 gene alterations and/or MYC amplifications was considered the most reliable prognostic factor. However, recent molecular analyses have subdivided SHH MB into several subtypes with distinct characteristics such as age, TP53 mutation, MYC amplification, presence of metastases, TERT promoter alterations, PTEN loss, and other chromosomal alterations as well as SHH pathway-related gene mutations. The third non-WNT/non-SHH MB (Group3/4) subgroup is genetically highly heterogeneous and displays several molecular patterns, including MYC and OTX2 amplification, GFI1B activation, KBTBD4 mutation, GFI1 rearrangement, PRDM6 enhancer hijacking, KDM6A mutation, LCA histology, chromosome 10 loss, isochromosome 17q, SNCAIP duplication, and CDK6 amplification. However, based on molecular profiling and methylation patterns, additional non-WNT/non-SHH MB subtypes have been described. Recent WHO (2021) guidelines stratified MB into four molecular subgroups with four and eight further subgroups for SHH and non-WNT/non-SHH MB, respectively. In this review, we discuss advancements in genetics, epigenetics, and transcriptomics for better characterization, prognostication, and treatment of MB using precision medicine.
髓母细胞瘤（MB）是最常见的儿童后颅窝恶性肿瘤。最近的遗传、表观遗传和转录组分析将 MB 分为三个亚组，Wingless 型（WNT）、Sonic Hedgehog（SHH）和非-WNT/非-SHH（最初称为第 3 组和第 4 组），具有不同的患者特征和预后。WNT 是最不常见的亚组，预后最好，其特征为核 β-连环蛋白表达、Catenin beta-1（CTNNB1）突变和 6 号染色体单体性。SHH 肿瘤包含 GLI1、GLI2、SUFU 和 PTCH1 基因的突变和改变，这些突变和改变持续激活 SHH 通路。最初，TP53 基因突变和/或 MYC 扩增被认为是最可靠的预后因素。然而，最近的分子分析已经将 SHH MB 细分为具有不同特征的几个亚型，如年龄、TP53 突变、MYC 扩增、转移存在、TERT 启动子改变、PTEN 缺失和其他染色体改变以及 SHH 通路相关基因突变。第三个非-WNT/非-SHH MB（第 3/4 组）亚组在遗传上高度异质性，并表现出几种分子模式，包括 MYC 和 OTX2 扩增、GFI1B 激活、KBTBD4 突变、GFI1 重排、PRDM6 增强子劫持、KDM6A 突变、LCA 组织学、10 号染色体缺失、17q 等臂染色体、SNCAIP 重复和 CDK6 扩增。然而，根据分子谱分析和甲基化模式，还描述了其他非-WNT/非-SHH MB 亚型。最近的世界卫生组织（2021 年）指南将 MB 分为四个分子亚组，SHH 和非-WNT/非-SHH MB 分别有四个和八个进一步的亚组。在这篇综述中，我们讨论了遗传学、表观遗传学和转录组学的进展，以更好地对 MB 进行特征描述、预后预测和治疗，采用精准医学方法。
