Medulloblastoma Comprises Four Distinct Molecular Variants
Medulloblastoma Comprises Four Distinct Molecular Variants
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DOI：
10.1200/jco.2009.27.4324
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发表时间：
2011-04-10
影响因子：
45.3
通讯作者：
Taylor, Michael D.
中科院分区：
文献类型：
--
作者：
Northcott, Paul A.;Korshunov, Andrey;Taylor, Michael D.
目的近年来基因组学研究表明髓母细胞瘤存在多种不同的亚型。我们研究了一个大的队列髓母细胞瘤，以确定有多少亚组的疾病存在，他们是如何不同的，亚组之间的重叠程度。MethodsWe确定基因表达谱和DNA拷贝数畸变为103原发性髓母细胞瘤。生物信息学工具用于基于数据集中最具信息量的基因的髓母细胞瘤亚组的分类发现。亚组特异性的签名基因的免疫组化被用来确定两个独立的组织microarrais.ResultsMultiple无监督分析的转录谱确定了以下四个不同的，非重叠的分子变异：WNT，SHH，C组和D组的294 nonoverlapping髓母细胞瘤的亚组隶属关系。对这四个亚组的监督分析显示了显著的亚组特异性人口统计学、组织学、转移状态和DNA拷贝数畸变。DKK 1（WNT），SFRP 1（SHH），NPR 3（C组）和KCNA 1（D组）的免疫组化可以可靠和独特地分类约98%的患者中的福尔马林固定髓母细胞瘤。C组患者（NPR 3阳性肿瘤）的无进展生存期和总生存期显着下降，无论其转移状态如何。结论我们对大型髓母细胞瘤队列的综合基因组学方法已经确定了四个不同的亚组，具有不同的人口统计学特征、临床表现、转录谱、遗传异常和临床结果。髓母细胞瘤可以通过免疫组化可靠地分配到亚组，从而使髓母细胞瘤亚分类广泛使用。未来对髓母细胞瘤的研究和临床试验的发展应考虑到这四种不同类型的髓母细胞瘤。J Clin Oncol 29：1408-1414. (C)2010年美国临床肿瘤学会
PurposeRecent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. We studied a large cohort of medulloblastomas to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups.MethodsWe determined gene expression profiles and DNA copy number aberrations for 103 primary medulloblastomas. Bioinformatic tools were used for class discovery of medulloblastoma subgroups based on the most informative genes in the data set. Immunohistochemistry for subgroup-specific signature genes was used to determine subgroup affiliation for 294 nonoverlapping medulloblastomas on two independent tissue microarrays.ResultsMultiple unsupervised analyses of transcriptional profiles identified the following four distinct, nonoverlapping molecular variants: WNT, SHH, group C, and group D. Supervised analysis of these four subgroups revealed significant subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for DKK1 (WNT), SFRP1 (SHH), NPR3 (group C), and KCNA1 (group D) could reliably and uniquely classify formalin-fixed medulloblastomas in approximately 98% of patients. Group C patients (NPR3-positive tumors) exhibited a significantly diminished progression-free and overall survival irrespective of their metastatic status.ConclusionOur integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome. Medulloblastomas can be reliably assigned to subgroups through immunohistochemistry, thereby making medulloblastoma subclassification widely available. Future research on medulloblastoma and the development of clinical trials should take into consideration these four distinct types of medulloblastoma. J Clin Oncol 29: 1408-1414. (C) 2010 by American Society of Clinical Oncology