Institute of Medical Science, Department of Medical Biophysics, University of Toronto, and Program in Genetics and Genome Biology, Department of Pediatric Laboratory Medicine, Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Cancer Res. 2010 Jan 1;70(1):160-71. doi: 10.1158/0008-5472.CAN-09-1902.
Osteosarcomas are copy number alteration (CNA)-rich malignant bone tumors. Using microarrays, fluorescence in situ hybridization, and quantitative PCR, we characterize a focal region of chr3q13.31 (osteo3q13.31) harboring CNAs in 80% of osteosarcomas. As such, osteo3q13.31 is the most altered region in osteosarcoma and contests the view that CNAs in osteosarcoma are nonrecurrent. Most (67%) osteo3q13.31 CNAs are deletions, with 75% of these monoallelic and frequently accompanied by loss of heterozygosity (LOH) in flanking DNA. Notably, these CNAs often involve the noncoding RNAs LOC285194 and BC040587 and, in some cases, a tumor suppressor gene that encodes the limbic system-associated membrane protein (LSAMP). Ubiquitous changes occur in these genes in osteosarcoma, usually involving loss of expression. Underscoring their functional significance, expression of these genes is correlated with the presence of osteo3q13.31 CNAs. Focal osteo3q13.31 CNAs and LOH are also common in cell lines from other cancers, identifying osteo3q13.31 as a generalized candidate region for tumor suppressor genes. Osteo3q13.31 genes may function as a unit, given significant correlation in their expression despite the great genetic distances between them. In support of this notion, depleting either LSAMP or LOC285194 promoted proliferation of normal osteoblasts by regulation of apoptotic and cell-cycle transcripts and also VEGF receptor 1. Moreover, genetic deletions of LOC285194 or BC040587 were also associated with poor survival of osteosarcoma patients. Our findings identify osteo3q13.31 as a novel region of cooperatively acting tumor suppressor genes.
骨肉瘤是拷贝数改变（CNA）丰富的恶性骨肿瘤。我们使用微阵列、荧光原位杂交和定量 PCR 来描述 chr3q13.31（osteo3q13.31）上的一个焦点区域，该区域在 80%的骨肉瘤中存在 CNA。因此，osteo3q13.31 是骨肉瘤中改变最严重的区域，这与骨肉瘤中的 CNA 是非重现性的观点相矛盾。大多数（67%）的 osteo3q13.31 CNA 是缺失，其中 75%是单等位基因缺失，并且经常伴有侧翼 DNA 的杂合性丢失（LOH）。值得注意的是，这些 CNA 通常涉及非编码 RNA LOC285194 和 BC040587，并且在某些情况下，涉及编码边缘系统相关膜蛋白（LSAMP）的肿瘤抑制基因。这些基因在骨肉瘤中经常发生普遍变化，通常涉及表达缺失。这些基因的表达与 osteo3q13.31 CNA 的存在相关，强调了它们的功能意义。在来自其他癌症的细胞系中也经常发生焦点 osteo3q13.31 CNA 和 LOH，将 osteo3q13.31 鉴定为肿瘤抑制基因的一般候选区域。骨肉瘤中也常见 osteo3q13.31 基因的缺失和 LOH，这表明这些基因可能作为一个整体发挥作用，尽管它们之间存在很大的遗传距离，但它们的表达具有显著的相关性。支持这一观点的是，耗尽 LSAMP 或 LOC285194 均可通过调节凋亡和细胞周期转录物以及 VEGF 受体 1 促进正常成骨细胞的增殖。此外，LOC285194 或 BC040587 的遗传缺失也与骨肉瘤患者的不良预后相关。我们的研究结果确定了 osteo3q13.31 作为一个新的协同作用的肿瘤抑制基因区域。
