Buckley Patrick G, Alcock Leah, Bryan Kenneth, Bray Isabella, Schulte Johannes H, Schramm Alexander, Eggert Angelika, Mestdagh Pieter, De Preter Katleen, Vandesompele Jo, Speleman Frank, Stallings Raymond L
Department of Cancer Genetics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Clin Cancer Res. 2010 Jun 1;16(11):2971-8. doi: 10.1158/1078-0432.CCR-09-3215. Epub 2010 Apr 20.
The purpose of this study was to further define the biology of the 11q- neuroblastoma tumor subgroup by the integration of array-based comparative genomic hybridization with microRNA (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 array-based comparative genomic hybridization and for the expression of 430 miRNAs. A 15-miRNA expression signature previously shown 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 that differed significantly in 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 upregulated in unfavorable tumors, were predicted to target downregulated 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 show 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 event-free survival and overall survival outcomes than 11q status by itself, improving patient stratification.
本研究的目的是通过将基于芯片的比较基因组杂交与微小RNA（miRNA）表达谱数据相结合，进一步明确11q-神经母细胞瘤肿瘤亚组的生物学特性，以确定是否有可能改善患者分层。
通过基于芯片的比较基因组杂交和430种miRNA的表达分析，对一组广泛代表所有遗传亚型的原发性神经母细胞瘤（n = 160）进行了研究。使用先前显示可预测临床结果的15-miRNA表达特征分析了一个独立的11q-肿瘤队列（n = 37）。
11q-肿瘤中4p缺失和7q增益的发生频率显著更高，进一步明确了该亚型的遗传特征。使用miRNA表达生存特征可将11q-肿瘤分为两个亚组，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有显著差异，生存较差的亚组失衡明显更多。来自表达特征的miRNA在不良肿瘤中上调，预计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，表明这些miRNA可能有助于调节特征内的基因。
我们表明存在两种不同的伴有11q缺失的神经母细胞瘤生物学亚型，它们在miRNA表达谱、节段性失衡频率和临床结果方面存在差异。与单独的11q状态相比，miRNA表达特征与节段性失衡分析相结合，能更好地预测无事件生存和总生存结果，从而改善患者分层。
