Characterization of Canine Osteosarcoma by Array Comparative Genomic Hybridization and RT-qPCR: Signatures of Genomic Imbalance in Canine Osteosarcoma Parallel the Human Counterpart
Characterization of Canine Osteosarcoma by Array Comparative Genomic Hybridization and RT-qPCR: Signatures of Genomic Imbalance in Canine Osteosarcoma Parallel the Human Counterpart
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DOI：
10.1002/gcc.20908
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发表时间：
2011-11-01
影响因子：
3.7
通讯作者：
Breen, Matthew
中科院分区：
文献类型：
--
作者：
Angstadt, Andrea Y.;Motsinger-Reif, Alison;Breen, Matthew
骨肉瘤(Osteosaroma，OS)是人类和狗最常见的恶性骨肿瘤，具有极其复杂的核型，表现出高频率的基因组失衡。使用阵列比较基因组杂交(ACGH)评估人类OS的基因组特征有助于揭示导致疾病表型的遗传机制。以前对犬OS进行的低分辨率(10-20Mb)aCGH分析发现了广泛的反复DNA拷贝数异常，表明广泛的基因组不稳定。在这项研究中，我们用1Mb分辨率的aCGH描述了123个犬OS肿瘤，以生成一个数据集，用于与当前人类OS的数据进行直接比较，得出结论：犬和人类OS中的几个高频像差是同源的。为了确保基因注释的完整覆盖，我们确定了映射到这些同源异常狗区域的人类refseq基因，并发现了几个候选基因，证明了OS的参与。特别是，对RUNX2、TUSC3和PTEN的后续序列FISH和qRT-PCR分析表明，RUNX2、TUSC3和PTEN的表达水平与基因组拷贝数状态相关，表明RUNX2是OS相关基因，TUSC3可能是肿瘤抑制候选基因。这些数据共同证明了基因组比较肿瘤学识别基因突变的能力，这可能是OS进展的重要因素。对犬类OS基因组失衡的大规模筛查进一步证实了犬作为适合人类癌症的模型的使用，支持了在犬类癌症中发现的调控失调将为人类同行提供补充研究的途径的想法。(C)2011年Wiley-Liss，Inc.
Osteosarcoma (OS) is the most commonly diagnosed malignant bone tumor in humans and dogs, characterized in both species by extremely complex karyotypes exhibiting high frequencies of genomic imbalance. Evaluation of genomic signatures in human OS using array comparative genomic hybridization (aCGH) has assisted in uncovering genetic mechanisms that result in disease phenotype. Previous low-resolution (10-20 Mb) aCGH analysis of canine OS identified a wide range of recurrent DNA copy number aberrations, indicating extensive genomic instability. In this study, we profiled 123 canine OS tumors by 1 Mb-resolution aCGH to generate a dataset for direct comparison with current data for human OS, concluding that several high frequency aberrations in canine and human OS are orthologous. To ensure complete coverage of gene annotation, we identified the human refseq genes that map to these orthologous aberrant dog regions and found several candidate genes warranting evaluation for OS involvement. Specifically, subsequenct FISH and qRT-PCR analysis of RUNX2, TUSC3, and PTEN indicated that expression levels correlated with genomic copy number status, showcasing RUNX2 as an OS associated gene and TUSC3 as a possible tumor suppressor candidate. Together these data demonstrate the ability of genomic comparative oncology to identify genetic abberations which may be important for OS progression. Large scale screening of genomic imbalance in canine OS further validates the use of the dog as a suitable model for human cancers, supporting the idea that dysregulation discovered in canine cancers will provide an avenue for complementary study in human counterparts. (C) 2011 Wiley-Liss, Inc.