O'Hagan Rónán C, Chang Sandy, Maser Richard S, Mohan Ramya, Artandi Steven E, Chin Lynda, DePinho Ronald A
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Cancer Cell. 2002 Aug;2(2):149-55. doi: 10.1016/s1535-6108(02)00094-6.
Telomere dysfunction and associated fusion-breakage in the mouse encourages epithelial carcinogenesis and a more humanized genomic profile that includes nonreciprocal translocations (NRTs). Here, array comparative genomic hybridization was used to determine the pathogenic significance of NRTs and to determine whether telomere dysfunction also drives amplifications and deletions of cancer-relevant loci. Compared to tumors arising in mice with intact telomeres, tumors with telomere dysfunction possessed higher levels of genomic instability and showed numerous amplifications and deletions in regions syntenic to human cancer hotspots. These observations suggest that telomere-based crisis provides a mechanism of chromosomal instability, including regional amplifications and deletions, that drives carcinogenesis. This model provides a platform for discovery of genes responsible for the major cancers affecting aged humans.
小鼠中的端粒功能障碍及相关的融合-断裂会促进上皮癌发生，并形成更具人类特征的基因组图谱，其中包括非相互易位（NRTs）。在此，利用阵列比较基因组杂交来确定NRTs的致病意义，并确定端粒功能障碍是否也会驱动癌症相关基因座的扩增和缺失。与端粒完整的小鼠所产生的肿瘤相比，端粒功能障碍的肿瘤具有更高水平的基因组不稳定性，并且在与人类癌症热点区域同源的区域显示出大量的扩增和缺失。这些观察结果表明，基于端粒的危机提供了一种染色体不稳定性机制，包括区域扩增和缺失，从而驱动癌症发生。该模型为发现导致影响老年人类的主要癌症的基因提供了一个平台。
