Analysis of glioblastoma stem cell derived from bone marrow stem cell using high-resolution array-based comparative genomic hybridization

尽管在基础生命科学和临床研究方面付出了巨大的努力，但在改善胶质母细胞瘤患者预后方面进展甚微。由于胶质瘤的高浸润性，手术治疗在实践中是不可能的。临床过程取决于肿瘤细胞的生物学行为。越来越多的证据表明，遗传和表观遗传改变的积累对肿瘤的发生和发展至关重要。常规比较基因组杂交（中期- cgh）_4已广泛用于筛选肿瘤全基因组的染色体增减。基于微阵列的CGH （array-CGH）是最近发展起来的一种基因组分析技术，它能够高通量筛选基因畸变，并敏感地检测单基因拷贝变化。在这项研究中，我们采用阵列CGH形成胶质母细胞瘤的拷贝数改变，并分析基因组变化与预后的潜在相关性。我们通过基于阵列的比较基因组杂交分析检查了胶质母细胞瘤活检样本的全基因组畸变。拷贝数增加频率最高的是RFC2（73.3%）、EGFR（63.2%）和FGR、ELN、CDKN1C、FES、TOP2A和ARSA（各57.9%）。拷贝数丢失频率最高的基因为TBR1（52.6%）、BMI1（52.6%）、EGR2（47.4%）、DMBT1（47.4%）、MTAP（42.1%）和FGFR2（42.1%）。CDKN1C和INS拷贝数的增加和TBR1拷贝数的损失与患者的生存期延长显著相关。在EGFR、SAS/CDK4、PDGFRA、MDM2和ARSA上鉴定出高水平扩增。这些基因被认为参与了胶质母细胞瘤的发生和发展。本研究表明，基于阵列的比较基因组杂交分析在评估脑肿瘤的拷贝数变化和染色体区域改变方面具有很大的潜力。此外，我们表明全基因组拷贝数谱的非线性分析方法可能提供胶质母细胞瘤患者的预后信息。少

Dpite great efforts in basic life science and clinical esearch, little progress has been made in mproving the prognosis for patients with glioblastomas. urgical cure of gliomas is impossible in practice because of their high infiltrating activity. The clinical course is dependent upon the biological behavior of the tumor cells. There is increasing evidence that the accumulation of genetic and epigenetic alterations is essential for tumor initiation and progression. Conventional comparative genomic hybridization(metaphase-CGH)_4 has been widely used to screen for chromosomal gains and losses throughout the entiregenome of a tumor. Microarraybased CGH (array-CGH) is a recently developed genomicanalysis technology that enables high-throughputscreening of gene aberrations with sensitivity to detect single gene copy changes. In this study, we employed array CGH formapping of copy number alterations in glioblastomas and analyzed the potential correlation between genomic changes and prognosis … More of patients. We examined whole genomic aberrations of biopsied samples from glioblastomas by array-based comparative genomic hybridization analysis. The highest frequencies of copy number gains were observed on RFC2 (73.3%), EGFR (63.2%), and FGR, ELN, CDKN1C, FES, TOP2A, and ARSA (57.9% each). The highest frequencies of copy number losses were detected on TBR1(52.6%), BMI1 (52.6%), EGR2 (47.4%), DMBT1 (47.4%), MTAP (42.1%), and FGFR2 (42.1%). The copy numbergains of CDKN1C and INS and the copy number losses of TBR1 were significantly correlated with longer survival of patients. High-level amplifications were identified on EGFR, SAS/CDK4, PDGFRA, MDM2, and ARSA. These genes are assumed to be involved in tumorigenesis or progression of glioblastomas. The present study indicates that array-based comparative genomic hybridization analysis has great potential for assessment of copy number changes and altered chromosomal regions of brain tumors. Furthermore, we show that nonlinear analysis methods of whole genome copy number profiles may provide prognostic information about glioblastoma patients. Less