Kaur Sippy, Larramendy Marcelo L, Gentile Massimiliano, Svarvar Catarina, Koivisto-Korander Riitta, Vauhkonen Hanna, Scheinin Ilari, Leminen Arto, Bützow Ralf, Böhling Tom, Knuutila Sakari
Department of Pathology, Haartman Institute and HUSLAB, University of Helsinki and Helsinki University Central Hospital, P.O.B. 21, FI-00014 Helsinki, Finland.
Laboratorio de Citogenética y Cátedra de Citología, Facultad de Ciencias Naturales y Museo, Universidad Nacional de La Plata, 1900 La Plata, Argentina.
Cancer Genomics Proteomics. 2006 Nov-Dec;3(6):347-354. Epub 2006 Nov 1.
Resistance to chemotherapeutic agents and radiotherapy has kept surgery the primary treatment of uterine leiomyosarcoma (ULMS). In search of leads for potential therapeutic targets, array CGH (aCGH) was used to obtain a genomewide pattern of ULMS-specific genetic imbalances and to define the affected biological processes. Fine-resolution genomewide aCGH analysis was performed using customised 16K cDNA microarrays on 18 primary ULMS cases. Furthermore, patterns of DNA copy number changes were assessed for associations with clinical parameters, i.e., tumour grade, tumour size and patient status at last follow-up. Our aCGH results demonstrated extensive DNA copy number changes in all chromosomes. Of the 10,590 gene loci included in the analysis, 4,387 were found to be affected by DNA copy number gains and 4,518 by DNA copy number losses in at least one case. Further analyses revealed that 231 of these were commonly gained, and 265 lost in at least 20% of the cases. The gains affected loci at 1p, 1q, 2p, 3p, 6p, 8q, 10q and 18q, whereas losses were observed at 2q, 4q, 6p, 6q, 7p, 7q, 13q, 14p, 16q, 19p, Xp and Xq. Enrichment analysis of biological processes revealed the gained genes to be involved in the G1/S transition of mitotic cell cycle, co-translational protein targeting to membrane, actin filament polymerisation and positive regulation of cytokine biosynthesis, whereas the genes affected by losses were associated with DNA replication, chromatin modification, telomere maintenance, meiosis, mitosis and angiogenesis. These biological processes featured prominently two well-established tumour suppressors (BRCA2, EREG) and one proto-oncogene (GFI1). No statistically significant associations were found between the aberration patterns and clinical variables. Analysis of gene pathways using aCGH uncovered the biological networks involved in malignant progression of ULMS.
对化疗药物和放疗的耐药性使得手术仍然是子宫平滑肌肉瘤（ULMS）的主要治疗方法。为了寻找潜在治疗靶点的线索，采用阵列比较基因组杂交（aCGH）来获取ULMS特异性基因失衡的全基因组模式，并确定受影响的生物学过程。使用定制的16K cDNA微阵列对18例原发性ULMS病例进行了高分辨率全基因组aCGH分析。此外，评估了DNA拷贝数变化模式与临床参数的相关性，即肿瘤分级、肿瘤大小和最后随访时的患者状态。我们的aCGH结果显示所有染色体均存在广泛的DNA拷贝数变化。在分析中包含的10590个基因座中，至少在1例病例中发现4387个受DNA拷贝数增加影响，4518个受DNA拷贝数减少影响。进一步分析显示，其中231个在至少20%的病例中常见增加，265个常见减少。增加影响1p、1q、2p、3p、6p、8q、10q和18q的基因座，而在2q、4q、6p、6q、7p、7q、13q、14p、16q、19p、Xp和Xq观察到减少。生物学过程的富集分析显示，增加的基因参与有丝分裂细胞周期的G1/S转换、共翻译蛋白质靶向膜、肌动蛋白丝聚合和细胞因子生物合成的正调控，而受减少影响的基因与DNA复制、染色质修饰、端粒维持、减数分裂、有丝分裂和血管生成相关。这些生物学过程中突出显示了两个公认的肿瘤抑制因子（BRCA2、EREG）和一个原癌基因（GFI1）。在畸变模式与临床变量之间未发现统计学上的显著关联。使用aCGH对基因通路进行分析揭示了参与ULMS恶性进展的生物学网络。
