一个由美国、英国、以色列等国组成的研究团队建立了一种染色体不稳定的小鼠模型，这种模型与人类的癌症发生有很多相似之处。
达那-法伯癌症研究所（the Dana-Farber Cancer Institute）的科学家开发了一种更接近人类癌症的老鼠模型（mouse model），此模型将协助研究人员更容易找到致癌基因，并能改善实验室中癌症药物试验的预测值。此研究由Ronald A. Depinhho医师主导，并结合了Lynda Chin医师的高解析CGH矩阵，这是一种基因组扫瞄技术能找出基因组中异常的DNA，此研究发表于5月21日的Nature期刊网络版。
DePinho医师表示：“在老鼠与人类肿瘤中找到相同的异常基因样式（patterns），显示这两个物种在癌症机制可能极为类似，可通过老鼠模型找出可能的癌症基因，了解这些基因在形成肿瘤时所扮演的角色，并找到可能的治疗方法。”传统上，癌症研究的老鼠模型是将致癌基因送入老鼠胚胎，让老鼠经由人工的方法得到癌症，并不是自然产生癌症。这种老鼠的肿瘤缺乏人类肿瘤的关键的特异性，例如：基因组的不稳定性（genomic instability），包括染色体断裂或重组等，都会导致基因的异常或遗失，有些甚至会造成基因的重复复制进而产生肿瘤。
此研究中，研究人员利用基因敲除（knockout）的方法，使老鼠细胞内缺乏一些重要的分子，造成老鼠基因组产生不稳定的现象，结果老鼠便产生T细胞急性淋巴癌（T-cell acute lymphoblastic leukemia/lymphoma，T-ALL），可发现许多复合性的突变样式，包括：染色体重组、基因扩大（gene amplifications）以及基因被删除等现象。目前研究人员已在T-ALL老鼠模型中鉴定出两个基因，FBXW7以及PTEN，是在人类癌症中最常被突变或被删除的基因。
Chin实验室的研究成员在过去数年来，已经将老鼠染色体的变异与人类肿瘤样本进行比对，至少超过400多种癌症，包括：黑色素瘤、肺癌、结肠癌、胰脏癌以及多种骨髓癌等。比对中显示：老鼠癌细胞中基因的不稳定性，在很多情况下都会造成DNA改变，且情况类似于人类的肿瘤细胞。因此，研究人员建议这个新的老鼠模型可用于人类癌症的研究。（生物谷援引生命经纬）
原始出处:
Nature advance online publication 21 May 2007 | doi:10.1038/nature05886; Received 26 March 2007; Accepted 30 April 2007; Published online 21 May 2007
Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers
Richard S. Maser1,14, Bhudipa Choudhury4,14, Peter J. Campbell4,14, Bin Feng2,14, Kwok-Kin Wong1, Alexei Protopopov2, Jennifer O'Neil3, Alejandro Gutierrez3,5, Elena Ivanova2, Ilana Perna2, Eric Lin6, Vidya Mani1, Shan Jiang1, Kate McNamara1, Sara Zaghlul1, Sarah Edkins4, Claire Stevens4, Cameron Brennan7, Eric S. Martin1, Ruprecht Wiedemeyer1, Omar Kabbarah1, Cristina Nogueira1, Gavin Histen8, Jon Aster8, Marc Mansour11, Veronique Duke11, Letizia Foroni11, Adele K. Fielding11, Anthony H. Goldstone12, Jacob M. Rowe13, Yaoqi A. Wang1,2, A. Thomas Look3, Michael R. Stratton4, Lynda Chin1,2,9, P. Andrew Futreal4 & Ronald A. DePinho1,2,10
Department of Medical Oncology,
Center for Applied Cancer Science of the Belfer Institute for Innovative Cancer Science,
Department of Pediatric Oncology Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Division of Hematology, Children's Hospital, Boston, Massachusetts 02115, USA
Agilent Technologies, Palo Alto, California 94304, USA
Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
Department of Pathology,
Department of Dermatology,
Department of Genetics and Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
Royal Free and University College Medical School, London NW3 2PF, UK
University College London Hospitals, London NW1 2BU, UK
Rambam Medical Center and Technion, Haifa 31096, Israel
These authors contributed equally to this work.
Correspondence to: Ronald A. DePinho1,2,10 Correspondence and requests for materials should be addressed to R.A.D. (Email: ron_depinho@dfci.harvard.edu).
Abstract
Highly rearranged and mutated cancer genomes present major challenges in the identification of pathogenetic events driving the neoplastic transformation process. Here we engineered lymphoma-prone mice with chromosomal instability to assess the usefulness of mouse models in cancer gene discovery and the extent of cross-species overlap in cancer-associated copy number aberrations. Along with targeted re-sequencing, our comparative oncogenomic studies identified FBXW7 and PTEN to be commonly deleted both in murine lymphomas and in human T-cell acute lymphoblastic leukaemia/lymphoma (T-ALL). The murine cancers acquire widespread recurrent amplifications and deletions targeting loci syntenic to those not only in human T-ALL but also in diverse human haematopoietic, mesenchymal and epithelial tumours. These results indicate that murine and human tumours experience common biological processes driven by orthologous genetic events in their malignant evolution. The highly concordant nature of genomic events encourages the use of genomically unstable murine cancer models in the discovery of biological driver events in the human oncogenome.
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