Molecular characterization of the pediatric preclinical testing panel.
Molecular characterization of the pediatric preclinical testing panel.
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DOI：
10.1158/1078-0432.ccr-07-5090
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发表时间：
2008-07-15
期刊：
影响因子：
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通讯作者：
Houghton PJ
中科院分区：
文献类型：
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作者：
Neale G;Su X;Morton CL;Phelps D;Gorlick R;Lock RB;Reynolds CP;Maris JM;Friedman HS;Dome J;Khoury J;Triche TJ;Seeger RC;Gilbertson R;Khan J;Smith MA;Houghton PJ
鉴定用于治疗儿童癌症的新型治疗剂需要临床前模型，该模型概括了其各自临床组织型的分子特征。在此，我们将Affyandroid HG-U133 Plus 2分析应用于儿科临床前测试项目中的扩展模型组。分析导致排除了两种小鼠来源的肿瘤细胞系和五种不与人或异种移植骨肉瘤样品聚集的骨肉瘤细胞系。我们比较了其余87个模型的表达谱与来自112个代表相同组织学的临床样本的表达谱，并显示一旦从分析中消除“免疫监视”基因（由临床样本中浸润的免疫细胞贡献），模型肿瘤与适当的临床组织型聚类。使用Affyestival 100 K单核苷酸多态性基因芯片分析拷贝数改变表明，模型具有与其临床对应物相似的拷贝数改变。发现了先前未报道的几个一致的拷贝数变化（例如，在7个胶质母细胞瘤样品中的5个中观察到22q11.21的增加，在9个尤文氏肉瘤模型中的5个和12个横纹肌肉瘤模型中的4个中观察到16q22.3的缺失，以及在7个骨肉瘤模型中的5个中观察到21q22.3的扩增）。然后，我们询问拷贝数的变化是否反映了基因表达的坐标变化。我们鉴定了493个拷贝数改变的基因，这些基因是非随机的，似乎可以鉴定遗传改变的组织型特异性程序。这些数据表明，临床前模型准确地概括了儿童癌症常见的表达谱和遗传改变，支持其在药物开发中的价值。
Identifying novel therapeutic agents for the treatment of childhood cancers requires preclinical models that recapitulate the molecular characteristics of their respective clinical histotypes. Here, we have applied Affymetrix HG-U133Plus2 profiling to an expanded panel of models in the Pediatric Preclinical Testing Program. Profiling led to exclusion of two tumor lines that were of mouse origin and five osteosarcoma lines that did not cluster with human or xenograft osteosarcoma samples. We compared expression profiles of the remaining 87 models with profiles from 112 clinical samples representing the same histologies and show that model tumors cluster with the appropriate clinical histotype, once “immunosurveillance” genes (contributed by infiltrating immune cells in clinical samples) are eliminated from the analysis. Analysis of copy number alterations using the Affymetrix 100K single nucleotide polymorphism GeneChip showed that the models have similar copy number alterations to their clinical counterparts. Several consistent copy number changes not reported previously were found (e.g., gain at 22q11.21 that was observed in 5 of 7 glioblastoma samples, loss at 16q22.3 that was observed in 5 of 9 Ewing’s sarcoma and 4 of 12 rhabdomyosarcoma models, and amplification of 21q22.3 that was observed in 5 of 7 osteosarcoma models). We then asked whether changes in copy number were reflected by coordinate changes in gene expression. We identified 493 copy number – altered genes that are nonrandom and appear to identify histotype-specific programs of genetic alterations. These data indicate that the preclinical models accurately recapitulate expression profiles and genetic alterations common to childhood cancer, supporting their value in drug development.