文章：

髓母细胞组学：开始的结束

Medulloblastomics: the end of the beginning

原文发布日期：2012-11-23

DOI: 10.1038/nrc3410

类型: Review Article

开放获取: 否

要点：

1. Medulloblastoma is the most common malignant paediatric brain tumour and is a leading cause of cancer-related morbidity and mortality in children.
2. Integrative genomic studies have recently identified at least four distinct molecular subgroups of medulloblastoma — WNT, sonic hedgehog (SHH), Group 3 and Group 4 — which exhibit highly discriminate transcriptional, cytogenetic and mutational spectra in addition to divergent patient demographics and clinical behaviour.
3. Recent next-generation sequencing of medulloblastoma samples and their matched constitutional DNA has led to the identification of a multitude of previously unknown candidate genes that are somatically mutated in this cancer, including many that are mutated in a subgroup-specific manner.
4. Different mechanisms of structural variation, including somatic copy number aberrations, chromothripsis and tetraploidy, contribute to a considerable proportion of medulloblastomas and may be more prevalent than recurrent somatic mutations in Group 3 and Group 4 tumours.
5. Despite the extensive amount of copy number and sequence data that has become available for large cohorts of medulloblastoma, most Group 3 and Group 4 tumours cannot be attributed to a specific driver mutation or mutations, suggesting that additional mechanisms, such as epigenetic deregulation, may also have a prominent role.
6. Research on medulloblastoma during the next few years will be focused on the functional validation of candidate genes and molecular processes that were reported to be deregulated in the recent human genomic studies. The generation of faithful models that recapitulate these mutational events will become a priority, and such reagents will be a valuable resource for the development of rational, molecularly targeted therapies.

要点翻译：

1. 髓母细胞瘤是最常见的小儿恶性脑瘤，也是导致儿童癌症相关发病和死亡的主要原因。
2. 整合基因组学研究近期识别出至少四种不同的髓母细胞瘤分子亚群——WNT、声波刺猬（SHH）、第3组和第4组——这些亚群除了表现出不同的患者人口统计学特征和临床行为外，还呈现高度差异化的转录组、细胞遗传学和突变谱。
3. 近期对髓母细胞瘤样本及其匹配的体质DNA进行的新一代测序，使得大量此前未知的在该癌症中发生体细胞突变的候选基因被识别出来，其中许多基因以亚群特异性方式发生突变。
4. 结构变异的不同机制，包括体细胞拷贝数异常、染色体碎裂和四倍体，导致了相当比例的髓母细胞瘤，并且在第3组和第4组肿瘤中可能比复发性体细胞突变更为普遍。
5. 尽管已获得大量髓母细胞瘤大群体的拷贝数和序列数据，但大多数第3组和第4组肿瘤无法归因于特定的驱动突变，这表明其他机制，如表观遗传失调，可能也起着重要作用。
6. 未来几年对髓母细胞瘤的研究将集中于近期人类基因组研究中报道的失调候选基因和分子过程的功能验证。构建能重现这些突变事件的可靠模型将成为优先任务，此类工具将为开发合理的分子靶向疗法提供宝贵资源。

英文摘要：

The division of medulloblastoma into different subgroups by microarray expression profiling has dramatically changed our perspective of this malignant childhood brain tumour. Now, the availability of next-generation sequencing and complementary high-density genomic technologies has unmasked novel driver mutations in each medulloblastoma subgroup. The implications of these findings for the management of patients are readily apparent, pinpointing previously unappreciated diagnostic and therapeutic targets. In this Review, we summarize the 'explosion' of data emerging from the application of modern genomics to medulloblastoma, and in particular the recurrent targets of mutation in medulloblastoma subgroups. These data are currently making their way into clinical trials as we seek to integrate conventional and molecularly targeted therapies.

摘要翻译： 

通过微阵列表达谱将髓母细胞瘤划分为不同亚组，极大地改变了我们对这种恶性儿童脑瘤的认识。如今，新一代测序技术以及配套的高密度基因组学技术，揭示了每个髓母细胞瘤亚组中新的驱动突变。这些发现对患者管理的意义显而易见，指出了以往未被重视的诊断和治疗靶点。在本综述中，我们总结了现代基因组学应用于髓母细胞瘤所带来的“数据爆炸”，特别是各亚组中反复出现的突变靶点。目前，这些数据正逐步进入临床试验，我们致力于将传统治疗与分子靶向治疗相结合。

原文链接：

Medulloblastomics: the end of the beginning