Zhang Shulin, Lloyd Ruth, Bowden Gregory, Glickman Barry W, de Boer Johan G
Department of Biology, Centre for Environmental Health, University of Victoria, Victoria, BC, Canada V8W 3N5.
Mutat Res. 2002 Mar 20;500(1-2):67-74. doi: 10.1016/s0027-5107(01)00297-4.
Mismatch repair (MMR) genes, such as Msh2, are classified as "mutator" genes, responsible for the microsatellite instability identified in many tumors. In the current study, the mutation frequency and mutational spectrum in thymic lymphoma arising in Msh2 deficient mice are investigated. Thymic lymphoma developed in Msh2-/- background displayed an eight to nine-fold increase in mutation frequency compared to the normal thymi in Msh2 deficient animals. Sequencing demonstrated significantly different mutational spectra between normal thymus tissue and thymic lymphomas in Msh2-/- mice (P=0.02). The tumor mutational spectrum is characterized by an increase in base substitutions occurring at A:T sites, and multiple mutations, as well as a minor increase in -1 frameshifts. We analyzed mutations in different parts of the tumors, and different regional hotspots could be identified. Several hotspot mutations that are a rare event in normal tissues were identified in the tumor tissues. We conclude that thymic lymphomas arising in Msh2 deficient genetic background are hypermutable and the altered mutational spectrum might be an indication of infidelity of DNA replication during tumorigenesis.
错配修复（MMR）基因，如Msh2，被归类为“突变”基因，负责许多肿瘤中鉴定出的微卫星不稳定性。在本研究中，对Msh2缺陷小鼠发生的胸腺淋巴瘤中的突变频率和突变谱进行了研究。与Msh2缺陷动物的正常胸腺相比，在Msh2 - / - 背景下发生的胸腺淋巴瘤的突变频率增加了八到九倍。测序显示Msh2 - / - 小鼠的正常胸腺组织和胸腺淋巴瘤之间的突变谱有显著差异（P = 0.02）。肿瘤突变谱的特征是A：T位点发生的碱基替换增加、多个突变以及-1移码的轻微增加。我们分析了肿瘤不同部位的突变，并确定了不同的区域热点。在肿瘤组织中鉴定出了一些在正常组织中罕见的热点突变。我们得出结论，在Msh2缺陷遗传背景下发生的胸腺淋巴瘤具有高度可突变性，并且改变的突变谱可能表明肿瘤发生过程中DNA复制的不忠实性。
