Characterization of novel and complex genomic aberrations in glioblastoma using a 32K BAC array
Characterization of novel and complex genomic aberrations in glioblastoma using a 32K BAC array
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DOI：
10.1215/15228517-2009-013
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发表时间：
2009-12-01
期刊：
影响因子：
15.9
通讯作者：
de Stahl, Teresita Diaz
中科院分区：
文献类型：
--
作者：
Nord, Helena;Hartmann, Christian;de Stahl, Teresita Diaz
胶质母细胞瘤是一种恶性中枢神经系统肿瘤，通常伴有破坏性症状。GB患者预后非常差，尽管进行了治疗，但大多数患者在诊断后12个月内死亡。RAS、肿瘤蛋白53 （TP53）、磷酸肌苷激酶3 （PIK3）通路以及细胞周期控制通路等多种通路已被发现在该肿瘤中被破坏。然而，新出现的数据表明，这些畸变只代表了神经胶质瘤形成过程中基因变化的一小部分。在这项研究中，我们采用了32K克隆基因组阵列，覆盖了99%的当前人类基因组组装，对一组78 gb的基因组进行了详细的遗传分析。鉴定出复杂的畸变模式，包括高拷贝数和窄拷贝数扩增子，以及许多纯合缺失的位点。在数量（平均3个）和大小（平均1.4 Mb）上变化的扩增子经常被检测到（81%的样本）。这些基因座不仅包括先前报道的致癌基因（EGFR、PDGFRA、MDM2和CDK4），还包括许多新的致癌基因，如GRB10、MKLN1、PPARGC1A、HGF、NAV3、CNTN1、SYT1和ADAMTSL3。另一方面，BNC2、PTPLAD2和PTPRE代表了包含在纯合缺失位点内的新的候选肿瘤抑制基因。其中许多基因已经与几种癌症有关；另一些则代表了新的候选基因，可能作为预后标记，甚至未来的治疗靶点。在样本之间观察到的巨大个体差异表明了疾病的潜在复杂性，并加强了基于患者遗传谱的个性化治疗的需求。神经肿瘤学11,803-818,2009(发表于神经肿瘤学[连载在线]，博士。D08-00228, 2009年3月20日。URL http://neuro-oncology。杜克journals.org;DOI: 10.1215 / 15228517-2009-013)
Glioblastomas (GBs) are malignant CNS tumors often associated with devastating symptoms. Patients with GB have a very poor prognosis, and despite treatment, most of them die within 12 months from diagnosis. Several pathways, such as the RAS, tumor protein 53 (TP53), and phosphoinositide kinase 3 (PIK3) pathways, as well as the cell cycle control pathway, have been identified to be disrupted in this tumor. However, emerging data suggest that these aberrations represent only a fraction of the genetic changes involved in gliomagenesis. In this study, we have applied a 32K clone-based genomic array, covering 99% of the current assembly of the human genome, to the detailed genetic profiling of a set of 78 GBs. Complex patterns of aberrations, including high and narrow copy number amplicons, as well as a number of homozygously deleted loci, were identified. Amplicons that varied both in number (three on average) and in size (1.4 Mb on average) were frequently detected (81% of the samples). The loci encompassed not only previously reported oncogenes (EGFR, PDGFRA, MDM2, and CDK4) but also numerous novel oncogenes as GRB10, MKLN1, PPARGC1A, HGF, NAV3, CNTN1, SYT1, and ADAMTSL3. BNC2, PTPLAD2, and PTPRE, on the other hand, represent novel candidate tumor suppressor genes encompassed within homozygously deleted loci. Many of these genes are already linked to several forms of cancer; others represent new candidate genes that may serve as prognostic markers or even as therapeutic targets in the future. The large individual variation observed between the samples demonstrates the underlying complexity of the disease and strengthens the demand for an individualized therapy based on the genetic profile of the patient. Neuro-Oncology 11, 803-818, 2009 (Posted to Neuro-Oncology [serial online], Doc. D08-00228, March 20, 2009. URL http://neuro-oncology. duke journals.org; DOI: 10.1215/15228517-2009-013)