Nature：解析成神经管细胞瘤基因组复杂性

7月25日，Nature杂志以开放论文的形式在线报道了，科学家对成神经管细胞瘤四个不同亚型的基因组特性的深入解析结果。

成神经管细胞瘤是一种侵袭性生长的肿瘤，起源于小脑和延髓/脑干中。它是儿童最常见的恶性脑肿瘤，并显示出显著的生物学和临床表现的异质性。尽管最近在治疗上获得进展，仍有约40％儿童患者的肿瘤复发，30％将死于该疾病。

即使是那些生存下来的患者，生活质量也显著降低。目前发现成神经管细胞瘤具有四个在临床症状，生物学特性和遗传背景上独特的亚型。带有激活的wingless信号通路的WNT亚型肿瘤，在目前治疗手段下具有良好的预后。SHH亚型肿瘤带有Hedgehog信号通路的激活，其预后比WNT亚型稍差。 人们对于第3和第4组肿瘤其分子特点还了解不多，也最缺少有效的治疗方法。人们目前仍不清楚，是什么遗传突变造成了这些亚型之间的独特差异。

作为国际癌症基因组协会（ICGC）PedBrain肿瘤项目的一部分，本研究对125例成神经管细胞瘤患者与正常人配对样本进行了综合性深入测序分析。在第3组和4组肿瘤亚型中，形成四倍体被认定为频繁的早期事件。而且，研究者观察到，病人的年龄和突变率之间呈正相关。

此外，研究者还发现，几个常见突变经常以亚类型特异性的模式出现，其中有些是已知的成神经管细胞瘤相关基因（CTNNB1，PTCH1，MLL2，SMARCA4），而有些基因（DDX3X，CTDNEP1，KDM6A TBR1）的突变以前没有发现与此类肿瘤的关联。

RNA测序证实了这些改变，并发现了，就目前所知，第一个成神经管细胞瘤融合基因的表达。在不同肿瘤亚型间，染色质修饰常常发生变异。这些结果增进了人类对成神经管细胞瘤的基因组复杂性和异质性的了解，并为研发成神经管细胞瘤（特别是第3，4亚型）新疗法，提供了一些潜在的靶点。

原文摘要：

Dissecting the genomic complexity underlying medulloblastoma

David T. W. Jones,Natalie J?ger,Marcel Kool,Thomas Zichner,Barbara Hutter,Marc Sultan,Yoon-Jae Cho,Trevor J. Pugh,Volker Hovestadt,Adrian M. Stütz,Tobias Rausch,Hans-J?rg Warnatz,Marina Ryzhova,Sebastian Bender,Dominik Sturm,Sabrina Pleier,Huriye Cin,Elke Pfaff,Laura Sieber,Andrea Wittmann,Marc Remke,Hendrik Witt,Sonja Hutter,Theophilos Tzaridis,Joachim Weischenfeld et al.

Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity1. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified2, 3. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens4. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis2. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges2, 3, 5. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour–normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.