Genornics identifies medulloblastoma subgroups that are enriched for specific genetic alterations
Genornics identifies medulloblastoma subgroups that are enriched for specific genetic alterations
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DOI：
10.1200/jco.2005.04.4974
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发表时间：
2006-04-20
影响因子：
45.3
通讯作者：
Gilbertson, RJ
中科院分区：
文献类型：
--
作者：
Thompson, MC;Fuller, C;Gilbertson, RJ
目的：传统的基因突变鉴定方法既昂贵又费力。尽管如此，如果我们要避免排斥有效的分子靶向治疗，我们必须在肿瘤中含有药物靶点突变的患者身上测试这些药物。我们假设基因表达谱可能是一种更快速、更经济的方法来识别含有特定遗传异常的肿瘤。材料和方法采用U133av2 Affymetrix寡核苷酸阵列生成46例髓母细胞瘤样本的基因表达谱，并采用实时逆转录酶聚合酶链反应（RT-PCR）和免疫组织化学方法进行验证。利用荧光原位杂交（FISH）和直接测序证实了遗传异常。结果基因表达谱的监督分析将成神经管细胞瘤分为5个不同的亚组（亚组A ~ E）。区分这些亚群的基因表达特征预测了关键分子改变的存在，我们随后通过基因序列分析和FISH证实了这一点。亚组特异性异常包括无翼（WNT）通路突变和6号染色体缺失（B亚组）以及Sonic Hedgehog （SHH）通路突变（D亚组）。实时RT-PCR分析基因表达谱，然后用于准确预测在另一组31个髓母细胞瘤中WNT和SHH通路突变的存在。结论全基因组表达谱可以将大肿瘤群体划分为富含特定遗传改变的亚组。这种方法可能最终有助于为分子靶向治疗的未来临床试验选择患者。
PurposeTraditional genetic approaches to identify gene mutations in cancer are expensive and laborious. Nonetheless, if we are to avoid rejecting effective molecular targeted therapies, we must test these drugs in patients whose tumors harbor mutations in the drug target. We hypothesized that gene expression profiling might be a more rapid and cost-effective method of identifying tumors that contain specific genetic abnormalities.Materials and MethodsGene expression profiles of 46 samples of medulloblastoma were generated using the U133av2 Affymetrix oligonucleotide array and validated using real-time reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Genetic abnormalities were confirmed using fluorescence in situ hybridization (FISH) and direct sequencing.ResultsUnsupervised analysis of gene expression profiles partitioned medulloblastomas into five distinct subgroups (subgroups A to E). Gene expression signatures that distinguished these subgroups predicted the presence of key molecular alterations that we subsequently confirmed by gene sequence analysis and FISH. Subgroup-specific abnormalities included mutations in the Wingless (WNT) pathway and deletion of chromosome 6 (subgroup B) and mutations in the Sonic Hedgehog (SHH) pathway (subgroup D). Real-time RT-PCR analysis of gene expression profiles was then used to predict accurately the presence of mutations in the WNT and SHH pathways in a separate group of 31 medulloblastomas.ConclusionGenome-wide expression profiles can partition large tumor cohorts into subgroups that are enriched for specific genetic alterations. This approach may assist ultimately in the selection of patients for future clinical trials of molecular targeted therapies.