DNA breaks at fragile sites generate oncogenic RET/PTC rearrangements in human thyroid cells
DNA breaks at fragile sites generate oncogenic RET/PTC rearrangements in human thyroid cells
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DOI：
10.1038/onc.2009.502
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发表时间：
2010-04-01
期刊：
影响因子：
8
通讯作者：
Wang, Y-H
中科院分区：
文献类型：
--
作者：
Gandhi, M.;Dillon, L. W.;Wang, Y-H
人类染色体脆性位点是基因组中易于发生DNA断裂的区域，根据其在人群中的频率分为常见或罕见。常见的脆性位点经常与致癌染色体易位相关基因的位置一致，表明它们在癌症形成中的作用。然而，没有直接证据表明脆性位点的断裂与癌症特异性易位的形成有关。在这里，我们研究了脆性位点参与RET/PTC重排的形成，这是常见于甲状腺乳头状癌（PTC）。这些重排通常与辐射暴露有关;然而，在成人中发现的大多数肿瘤与辐射无关。在这项研究中，我们提供了结构和生化证据，证明参与两种主要类型RET/PTC重排的RET、CCDC 6和NCOA 4基因位于常见的脆性位点FRA 10 C和FRA 10 G，并在暴露于脆性位点后发生DNA断裂诱导化学物质。此外，人类甲状腺细胞暴露于这些化学物质导致癌症特异性RET/PTC重排的形成。这些结果为染色体脆性位点参与人类细胞中癌症特异性重排的产生提供了直接证据。Oncogene（2010）29，2272-2280; doi：10.1038/onc.2009.502; 2010年1月25日在线发表
Human chromosomal fragile sites are regions of the genome that are prone to DNA breakage, and are classified as common or rare, depending on their frequency in the population. Common fragile sites frequently coincide with the location of genes involved in carcinogenic chromosomal translocations, suggesting their role in cancer formation. However, there has been no direct evidence linking breakage at fragile sites to the formation of a cancer-specific translocation. Here, we studied the involvement of fragile sites in the formation of RET/PTC rearrangements, which are frequently found in papillary thyroid carcinoma (PTC). These rearrangements are commonly associated with radiation exposure; however, most of the tumors found in adults are not linked to radiation. In this study, we provide structural and biochemical evidence that the RET, CCDC6 and NCOA4 genes participating in two major types of RET/PTC rearrangements, are located in common fragile sites FRA10C and FRA10G, and undergo DNA breakage after exposure to fragile site-inducing chemicals. Moreover, exposure of human thyroid cells to these chemicals results in the formation of cancer-specific RET/PTC rearrangements. These results provide the direct evidence for the involvement of chromosomal fragile sites in the generation of cancer-specific rearrangements in human cells. Oncogene (2010) 29, 2272-2280; doi: 10.1038/onc.2009.502; published online 25 January 2010