Integrative Genomic Analysis of Medulloblastoma Identifies a Molecular Subgroup That Drives Poor Clinical Outcome
Integrative Genomic Analysis of Medulloblastoma Identifies a Molecular Subgroup That Drives Poor Clinical Outcome
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DOI：
10.1200/jco.2010.28.5148
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发表时间：
2011-04-10
影响因子：
45.3
通讯作者：
Pomeroy, Scott L.
中科院分区：
文献类型：
--
作者：
Cho, Yoon-Jae;Tsherniak, Aviad;Pomeroy, Scott L.
目的髓母细胞瘤是一种异质性肿瘤，是儿童最常见的恶性脑肿瘤。为了了解其异质性的分子特征，并确定是否这样的特点代表这种疾病的患者的危险因素，我们进行了一个综合的基因组分析的一个大系列的原发tumors.Patients和MethodsWe分析的mRNA转录组的194髓母细胞瘤和高密度单核苷酸多态性阵列和miRNA分析，分别对115和98。基于非负矩阵因子分析的mRNA表达数据聚类用于识别髓母细胞瘤的分子亚组; DNA拷贝数、miRNA谱和临床结果分别进行分析。我们还验证了我们的研究结果在三个以前发表的独立的髓母细胞瘤datasets.ResultsIdentified是髓母细胞瘤的六个分子亚组，每个具有独特的组合的数值和结构染色体畸变，全球影响mRNA和miRNA的表达。我们揭示了每个亚组作为一个整体对临床结果的相对贡献，并表明一个以前未鉴定的分子亚组，其特征在于基因上的c-MYC拷贝数增加和转录上的感光细胞途径的富集，以及miR-183类似于96类似于182表达的增加，与显著较低的事件发生率相关-结论我们的结果详细说明了髓母细胞瘤复杂的基因组异质性，并确定了一个以前未被认识的分子亚组的临床结果较差，应制定更有效的治疗策略。J Clin Oncol 29：1424- 1430. (C)2010年美国临床肿瘤学会
PurposeMedulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large series of primary tumors.Patients and MethodsWe profiled the mRNA transcriptome of 194 medulloblastomas and performed high-density single nucleotide polymorphism array and miRNA analysis on 115 and 98 of these, respectively. Non-negative matrix factorization-based clustering of mRNA expression data was used to identify molecular subgroups of medulloblastoma; DNA copy number, miRNA profiles, and clinical outcomes were analyzed for each. We additionally validated our findings in three previously published independent medulloblastoma data sets.ResultsIdentified are six molecular subgroups of medulloblastoma, each with a unique combination of numerical and structural chromosomal aberrations that globally influence mRNA and miRNA expression. Wereveal the relative contribution of each subgroup to clinical outcome as a whole and show that a previously unidentified molecular subgroup, characterized genetically by c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-183 similar to 96 similar to 182 expression, is associated with significantly lower rates of event-free and overall survivals.ConclusionOur results detail the complex genomic heterogeneity of medulloblastomas and identify a previously unrecognized molecular subgroup with poor clinical outcome for which more effective therapeutic strategies should be developed. J Clin Oncol 29: 1424- 1430. (C) 2010 by American Society of Clinical Oncology