Ferreira B I, Alonso J, Carrillo J, Acquadro F, Largo C, Suela J, Teixeira M R, Cerveira N, Molares A, Goméz-López G, Pestaña A, Sastre A, Garcia-Miguel P, Cigudosa J C
Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas (CNIO), and CIBER on Rare Diseases (CIBERER), Madrid, Spain.
Oncogene. 2008 Mar 27;27(14):2084-90. doi: 10.1038/sj.onc.1210845. Epub 2007 Oct 22.
Ewing's sarcoma (ES) is characterized by specific chromosome translocations, the most common being t(11;22)(q24;q12). Additionally, other type of genetic abnormalities may occur and be relevant for explaining the variable tumour biology and clinical outcome. We have carried out a high-resolution array CGH and expression profiling on 25 ES tumour samples to characterize the DNA copy number aberrations (CNA) occurring in these tumours and determine their association with gene-expression profiles and clinical outcome. CNA were observed in 84% of the cases. We observed a median number of three aberrations per case. Besides numerical chromosome changes, smaller aberrations were found and defined at chromosomes 5p, 7q and 9p. All CNA were compiled to define the smallest overlapping regions of imbalance (SORI). A total of 35 SORI were delimited. Bioinformatics analyses were conducted to identify subgroups according to the pattern of genomic instability. Unsupervised and supervised clustering analysis (using SORI as variables) segregated the tumours in two distinct groups: one genomically stable (< or =3 CNA) and other genomically unstable (>3 CNA). The genomic unstable group showed a statistically significant shorter overall survival and was more refractory to chemotherapy. Expression profile analysis revealed significant differences between both groups. Genes related with chromosome segregation, DNA repair pathways and cell-cycle control were upregulated in the genomically unstable group. This report elucidates, for the first time, data about genomic instability in ES, based on CNA and expression profiling, and shows that a genomically unstable group of Ewing's tumours is correlated with a significant poor prognosis.
尤因肉瘤（ES）的特征是特定的染色体易位，最常见的是t(11;22)(q24;q12)。此外，还可能出现其他类型的基因异常，这对于解释肿瘤生物学的多样性和临床结局具有重要意义。我们对25例ES肿瘤样本进行了高分辨率阵列比较基因组杂交（array CGH）和表达谱分析，以表征这些肿瘤中发生的DNA拷贝数畸变（CNA），并确定它们与基因表达谱及临床结局的关联。在84%的病例中观察到了CNA。我们观察到每个病例的畸变中位数为3个。除了染色体数目变化外，还在5号染色体短臂、7号染色体长臂和9号染色体短臂上发现并确定了较小的畸变。所有CNA被汇总以定义最小重叠失衡区域（SORI）。共划定了35个SORI。进行了生物信息学分析，以根据基因组不稳定性模式识别亚组。无监督和有监督聚类分析（以SORI作为变量）将肿瘤分为两个不同的组：一组基因组稳定（CNA≤3个），另一组基因组不稳定（CNA>3个）。基因组不稳定组的总生存期在统计学上显著缩短，并且对化疗更具耐药性。表达谱分析显示两组之间存在显著差异。与染色体分离、DNA修复途径和细胞周期调控相关的基因在基因组不稳定组中上调。本报告首次基于CNA和表达谱分析阐明了ES中基因组不稳定的数据，并表明基因组不稳定的尤因肿瘤组与显著不良预后相关。
