Chromosomal and microRNA expression patterns reveal biologically distinct subgroups of 11q- neuroblastoma.
Chromosomal and microRNA expression patterns reveal biologically distinct subgroups of 11q- neuroblastoma.
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DOI：
10.1158/1078-0432.ccr-09-3215
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发表时间：
2010-06-01
期刊：
影响因子：
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通讯作者：
Stallings RL
中科院分区：
文献类型：
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作者：
Buckley PG;Alcock L;Bryan K;Bray I;Schulte JH;Schramm A;Eggert A;Mestdagh P;De Preter K;Vandesompele J;Speleman F;Stallings RL
本研究的目的是通过将 aCGH 与 miRNA 表达谱数据相结合，进一步定义 11q− 神经母细胞瘤肿瘤亚组的生物学，以确定是否可以改进患者分层。通过 aCGH 分析了广泛代表所有遗传亚型的一组原发性神经母细胞瘤 (n=160) 以及 430 个 miRNA 的表达。先前证明可预测临床结果的 15 个 miRNA 表达特征被用来分析 11q− 肿瘤的独立队列 (n=37)。 11q−肿瘤中 4p 缺失和 7q 增加发生的频率明显更高，进一步定义了该亚型的遗传特征。 11q−肿瘤可以使用 miRNA 表达生存特征分为两个亚组，这两个亚组在临床结果和大规模基因组失衡的总体频率上都有显着差异，其中生存率低的亚组具有明显更多的不平衡。表达特征中在不利肿瘤中上调的 miRNA 预计会以高于预期的频率靶向已发表的临床结果 mRNA 表达分类器中下调的基因，这表明 miRNA 可能有助于特征内基因的调节。我们证明，存在两种不同的 11q 缺失神经母细胞瘤生物亚型，它们的 miRNA 表达谱、节段失衡频率和临床结果不同。 miRNA 表达特征与节段失衡分析相结合，比 11q 状态本身能够更好地预测 EFS 和 OS 结果，从而改善患者分层。
The purpose of this study was to further define the biology of the 11q− neuroblastoma tumor subgroup by the integration of aCGH with miRNA expression profiling data to determine if improved patient stratification is possible. A set of primary neuroblastoma (n=160) which was broadly representative of all genetic subtypes was analyzed by aCGH and for the expression of 430 miRNAs. A 15 miRNA expression signature previously demonstrated to be predictive of clinical outcome was used to analyze an independent cohort of 11q− tumors (n=37). Loss of 4p and gain of 7q occurred at a significantly higher frequency in the 11q−tumors, further defining the genetic characteristics of this subtype. The 11q− tumors could be split into two subgroups using a miRNA expression survival signature which differed significantly in both clinical outcome and the overall frequency of large scale genomic imbalances, with the poor survival subgroup having significantly more imbalances. MiRNAs from the expression signature which were up-regulated in unfavorable tumors were predicted to target down-regulated genes from a published mRNA expression classifier of clinical outcome at a higher than expected frequency, indicating the miRNAs might contribute to the regulation of genes within the signature. We demonstrate that two distinct biological subtypes of neuroblastoma with loss of 11q occur which differ in their miRNA expression profiles, frequency of segmental imbalances and clinical outcome. A miRNA expression signature, combined with an analysis of segmental imbalances, provides greater prediction of EFS and OS outcomes than 11q status by itself, improving patient stratification.