Wang Daolong, You Ming
Department of Surgery and the Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Cancer Res. 2005 Sep 15;65(18):8158-65. doi: 10.1158/0008-5472.CAN-05-1508.
A series of linkage studies was previously conducted to identify quantitative trait loci associated with chemically induced lung tumors. However, little is known of genetic susceptibility to spontaneously occurring lung tumorigenesis (SLT) in mice. In this study, we did a whole-genome linkage disequilibrium analysis for susceptibility to SLT in mice using approximately 135,900 single-nucleotide polymorphisms (SNPs) from the Roche and Genomic Institute of the Novartis Research Foundation SNP databases. A common set of 13 mouse strains was used, including 10 resistant strains (129X1/SvJ, AKR/J, C3H/HeJ, C57BL/6J, DBA/2J, NZB/BlnJ, CAST/EiJ, SPRET/EiJ, SM/J, and LP/J) and 3 susceptible strains (A/J, BALB/cJ, and NZW/LaCJ). Fisher exact test was used to assess the association between individual SNPs and susceptibility to SLT. Five regions, SLT1 to SLT5, were mapped on chromosomes 6, 7, 8, 19, and X, respectively. SLT1 to SLT5 showed a significant association with SLT under the empirical threshold (P < or = 0.004) derived from permutation tests. SNP versus SNP association tests indicated that these SLT regions were unlikely to be caused by population substructure. Thus, SLT1 to SLT5 seem to be novel loci controlling the susceptibility to spontaneously occurring lung cancer in mice. Our results provide, for the first time, an insight into the genetic control of spontaneously occurring lung tumorigenesis.
先前进行了一系列连锁研究，以确定与化学诱导的肺肿瘤相关的数量性状基因座。然而，对于小鼠自发发生的肺肿瘤形成（SLT）的遗传易感性知之甚少。在本研究中，我们使用来自罗氏公司和诺华研究基金会基因组研究所SNP数据库的约135,900个单核苷酸多态性（SNP），对小鼠SLT易感性进行了全基因组连锁不平衡分析。使用了一组共13种小鼠品系，包括10种抗性品系（129X1/SvJ、AKR/J、C3H/HeJ、C57BL/6J、DBA/2J、NZB/BlnJ、CAST/EiJ、SPRET/EiJ、SM/J和LP/J）和3种易感品系（A/J、BALB/cJ和NZW/LaCJ）。采用Fisher精确检验评估个体SNP与SLT易感性之间的关联。分别在6号、7号、8号、19号和X染色体上定位了5个区域，即SLT1至SLT5。在置换检验得出的经验阈值（P≤0.004）下，SLT1至SLT5与SLT显示出显著关联。SNP与SNP关联检验表明，这些SLT区域不太可能是由群体亚结构引起的。因此，SLT1至SLT5似乎是控制小鼠自发发生肺癌易感性的新基因座。我们的结果首次为自发发生的肺肿瘤形成的遗传控制提供了见解。
