Genome-wide array comparative genomic hybridization analysis reveals distinct amplifications in osteosarcoma.
Genome-wide array comparative genomic hybridization analysis reveals distinct amplifications in osteosarcoma.
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DOI：
10.1186/1471-2407-4-45
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发表时间：
2004-08-07
期刊：
影响因子：
3.8
通讯作者：
Rao PH
中科院分区：
文献类型：
--
作者：
Man TK;Lu XY;Jaeweon K;Perlaky L;Harris CP;Shah S;Ladanyi M;Gorlick R;Lau CC;Rao PH
骨肉瘤是一种高度恶性的骨肿瘤的儿童和年轻人。其特征是极其复杂的核型和高频率的染色体扩增。目前，只有对治疗的组织学反应（坏死程度）代表了预测非转移性骨肉瘤患者在最终手术时结局的金标准。坏死程度较低的患者即使在化疗和原发肿瘤完全切除后，复发和预后不良的风险也较高。因此，更好地了解导致肿瘤发生和进展的潜在分子遗传事件可能会导致潜在的诊断和治疗靶点的确定。我们使用全基因组筛选方法-基于阵列的比较基因组杂交（阵列CGH），以确定48例骨肉瘤患者的DNA拷贝数变化。本研究采用荧光原位杂交技术对部分扩增克隆进行了验证。克隆显示增益（79%）比损失（66%）更频繁。高水平扩增和纯合缺失分别占肿瘤基因组的28.6%和3.8%。在238个克隆中存在高水平扩增，其中约37%的克隆表现出重复扩增。最常扩增的克隆定位于1p36.32（PRDM 16）、6p21.1（CDC 5L、HSPCB、NFKBIE）、8 q24、12q14.3（IFNG）、16 p13（MGRN 1）和17p11.2（PMP 22、MYCD、SOX 1、ELAC 27）。我们通过FISH从6p 12-p21、8 q23-q24和17p11.2扩增子验证了一些扩增克隆。在32个克隆中观察到纯合缺失，只有7个克隆在不止一个病例中显示纯合缺失。这7个克隆分别定位于1q25.1（4例）、3p14.1（4例）、13q12.2（2例）、4p15.1（2例）、6 q12（2例）、6 q12（2例）和6q16.3（2例）。这项研究清楚地证明了阵列CGH在定义高分辨率DNA拷贝数变化和细化扩增中的实用性。阵列CGH技术结合人类基因组数据库的解析结果提示了获得或丢失克隆中可能存在的目的基因。
Osteosarcoma is a highly malignant bone neoplasm of children and young adults. It is characterized by extremely complex karyotypes and high frequency of chromosomal amplifications. Currently, only the histological response (degree of necrosis) to therapy represent gold standard for predicting the outcome in a patient with non-metastatic osteosarcoma at the time of definitive surgery. Patients with lower degree of necrosis have a higher risk of relapse and poor outcome even after chemotherapy and complete resection of the primary tumor. Therefore, a better understanding of the underlying molecular genetic events leading to tumor initiation and progression could result in the identification of potential diagnostic and therapeutic targets. We used a genome-wide screening method – array based comparative genomic hybridization (array-CGH) to identify DNA copy number changes in 48 patients with osteosarcoma. We applied fluorescence in situ hybridization (FISH) to validate some of amplified clones in this study. Clones showing gains (79%) were more frequent than losses (66%). High-level amplifications and homozygous deletions constitute 28.6% and 3.8% of tumor genome respectively. High-level amplifications were present in 238 clones, of which about 37% of them showed recurrent amplification. Most frequently amplified clones were mapped to 1p36.32 (PRDM16), 6p21.1 (CDC5L, HSPCB, NFKBIE), 8q24, 12q14.3 (IFNG), 16p13 (MGRN1), and 17p11.2 (PMP22 MYCD, SOX1,ELAC27). We validated some of the amplified clones by FISH from 6p12-p21, 8q23-q24, and 17p11.2 amplicons. Homozygous deletions were noted for 32 clones and only 7 clones showed in more than one case. These 7 clones were mapped to 1q25.1 (4 cases), 3p14.1 (4 cases), 13q12.2 (2 cases), 4p15.1 (2 cases), 6q12 (2 cases), 6q12 (2 cases) and 6q16.3 (2 cases). This study clearly demonstrates the utility of array CGH in defining high-resolution DNA copy number changes and refining amplifications. The resolution of array CGH technology combined with human genome database suggested the possible target genes present in the gained or lost clones.
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