Identification of tumor-specific molecular signatures in intracranial ependymoma and association with clinical characteristics
Identification of tumor-specific molecular signatures in intracranial ependymoma and association with clinical characteristics
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DOI：
10.1200/jco.2006.06.3701
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发表时间：
2006-11-20
影响因子：
45.3
通讯作者：
Sozzi, Gabriella
中科院分区：
文献类型：
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作者：
Modena, Piergiorgio;Lualdi, Elena;Sozzi, Gabriella
目的探讨颅内室管膜瘤的分子生物学特征。材料与方法分析24例原发性颅内室管膜瘤。对于基因组分析，使用基于微阵列的比较基因组杂交（CGH），并通过荧光原位杂交和杂合性缺失作图验证结果。我们使用微阵列、实时定量逆转录聚合酶链反应和选定基因的甲基化分析进行基因表达谱分析。我们应用类别比较分析将基因组和表达谱数据与临床特征进行比较。结果阵列CGH检测到不同数量的基因组失衡，揭示了多个复发性增益区域（包括2q23、7p21、12p、13q21.1和20p12）和缺失（包括5q31、6q26、7q36、15q21.1、16q24、17p13.3、19p13.2和22q13.3）。室管膜瘤特异性基因表达特征的特征在于发育和分化途径的同时异常表达，包括NOTCH和sonic hedgehog信号。我们确定了与肿瘤位置、患者发病年龄和复发风险显著相关的特异性差异不平衡基因组克隆和基因表达特征。综合基因组和表达谱分析使我们能够鉴定出在颅内室管膜瘤中表达失调的基因，例如假定的原癌基因YAP 1的过表达。（位于11q22）和SULT4A1基因的下调结论目前的探索性分子谱研究使我们能够改进先前报道的基因组不平衡的间隔，以鉴定新的获得和损失的限制区域，并鉴定与各种临床变量相关的分子特征。在独立数据集上验证这些结果代表了转化为临床环境之前的下一步。
Purpose To delineate clinically relevant molecular signatures of intracranial ependymoma.Materials and Methods We analyzed 24 primary intracranial ependymomas. For genomic profiling, microarray-based comparative genomic hybridization (CGH) was used and results were validated by fluorescent in situ hybridization and loss of heterozygosity mapping. We performed gene expression profiling using microarrays, real-time quantitative reverse transcriptase polymerase chain reaction, and methylation analysis of selected genes. We applied class comparison analyses to compare both genomic and expression profiling data with clinical characteristics.Results A variable number of genomic imbalances were detected by array CGH, revealing multiple regions of recurrent gain (including 2q23, 7p21, 12p, 13q21.1, and 20p12) and loss (including 5q31, 6q26, 7q36, 15q21.1, 16q24, 17p13.3, 19p13.2, and 22q13.3). An ependymoma-specific gene expression signature was characterized by the concurrent abnormal expression of developmental and differentiation pathways, including NOTCH and sonic hedgehog signaling. We identified specific differentially imbalanced genomic clones and gene expression signatures significantly associated with tumor location, patient age at disease onset, and retrospective risk for relapse. Integrated genomic and expression profiling allowed us to identify genes of which the expression is deregulated in intracranial ependymoma, such as overexpression of the putative proto-oncogene YAP1 (located at 11q22) and downregulation of the SULT4A1 gene (at 22q13.3).Conclusion The present exploratory molecular profiling study allowed us to refine previously reported intervals of genomic imbalance, to identify novel restricted regions of gain and loss, and to identify molecular signatures correlating with various clinical variables. Validation of these results on independent data sets represents the,next step before translation into the clinical setting.