Nagase H, Mao J H, de Koning J P, Minami T, Balmain A
University of California-San Francisco Comprehensive Cancer Center, 94143, USA.
Cancer Res. 2001 Feb 15;61(4):1305-8.
The development of cancer is influenced both by exposure to environmental carcinogens and by the host genetic background. Epistatic interactions between genes are important in determining phenotype in plant and animal systems and are likely to be major contributors to cancer susceptibility in humans. Several tumor modifier loci have been identified from studies of mouse models of human cancer, and genetic interactions between modifier loci have been detected by genome scanning using recombinant congenic strains of mice (R. Fijneman et al., Nat. Genet., 14: 465-467, 1996; T. van Wezel et al., Nat. Genet., 14: 468-470, 1996; W. N. Frankel et al., Nat. Genet., 14, 371-373, 1996). We demonstrate here that strong genetic interactions between skin tumor modifier loci can be detected by hierarchical whole genome scanning of a complete interspecific backcross [outbred Mus spretus X Mus musculus (NIH/Ola)]. A locus on chromosome 7 (Skts1) showed a highly significant interaction with Skts5 on chromosome 12 (P < 10(-16)), whereas additional significant interactions were detected between loci on chromosomes 4 and 5, and 16 and 15. Some of these quantitative trait loci and their interactions, in particular the Skts1-Skts5 interaction, were confirmed in two completely independent backcrosses using inbred spretus strains (SEG/Pas and SPRET/Ei) and NIH/Ola. These results, therefore, illustrate the general use of interspecific crosses between Mus musculus and Mus spretus for the detection of strong genetic interactions between tumor modifier genes.
癌症的发生既受环境致癌物暴露的影响，也受宿主遗传背景的影响。基因之间的上位性相互作用在决定植物和动物系统的表型方面很重要，并且很可能是人类癌症易感性的主要因素。通过对人类癌症小鼠模型的研究，已经鉴定出了几个肿瘤修饰基因座，并且使用重组近交系小鼠通过基因组扫描检测到了修饰基因座之间的遗传相互作用（R. Fijneman等人，《自然遗传学》，14: 465 - 467，1996；T. van Wezel等人，《自然遗传学》，14: 468 - 470，1996；W. N. Frankel等人，《自然遗传学》，14，371 - 373，1996）。我们在此证明，通过对完整种间回交[远交小家鼠X小家鼠（NIH/Ola）]进行分层全基因组扫描，可以检测到皮肤肿瘤修饰基因座之间强大的遗传相互作用。7号染色体上的一个基因座（Skts1）与12号染色体上的Skts5显示出高度显著的相互作用（P < 10^(-16)），而在4号和5号染色体以及16号和15号染色体上的基因座之间也检测到了其他显著的相互作用。其中一些数量性状基因座及其相互作用，特别是Skts1 - Skts5相互作用，在使用近交小家鼠品系（SEG/Pas和SPRET/Ei）和NIH/Ola的两个完全独立的回交中得到了证实。因此，这些结果说明了小家鼠和小家鼠之间的种间杂交在检测肿瘤修饰基因之间强大遗传相互作用方面的普遍用途。
