The role of Kras2 in lung tumor susceptibility

描述（由申请人提供）：大多数人类肿瘤起源于上皮组织的自我更新细胞。肺肿瘤是最致命的，仅在美国2003年就预计有15.2万人死于肺肿瘤。家族聚类的证据表明，强烈的遗传因素会导致肺癌风险，而且只有10-20%的吸烟者会患上肺癌。确定肺癌易感性的基因变异将有助于预测个体风险，并促进新型治疗或预防药物的开发。由于种系多态性的存在，一种特殊的小鼠（Mus spretus）对肺癌的发展具有遗传抗性。敏感鼠和耐药鼠之间的杂交将用于遗传方法来鉴定肺肿瘤耐药基因。通过在FVB背景下肺肿瘤易感KrasM2小鼠与耐药的鼠种之间进行大规模回交，可以获得广泛的数据库和组织/肿瘤库，从而促进这一分析。关于与肺癌发生和进展相关的基因组变化以及肺癌易感性的遗传基础的数据已经可用。这些数据暗示Kras2基因是肺肿瘤发展和易感性的主要决定因素。这种特殊的ras基因家族成员在人和小鼠肺肿瘤中都经常发生突变，是过去小鼠主要肺肿瘤易感位点的候选基因之一。两种工程小鼠模型将用于测试Kras2在肺肿瘤发展和易感性中的作用。其中一种涉及将Kras2突变等位基因敲入内源性位点（/<rasM2小鼠），导致100%的自发性肺肿瘤发生率，而无需致癌物治疗。另一种模型（HrasKI小鼠）涉及将hras1编码序列敲入Kras2位点。这些菌株与不同遗传背景的野生型小鼠的杂交将用于分析肺癌对Kras2突变的需求，并确定Kras2在肺肿瘤易感性中的作用。肺肿瘤易感性的连锁分析揭示了其他几个肺肿瘤耐药或易感性基因的存在，包括小鼠7号染色体上抑制同源小鼠肺肿瘤形成的位点（Ltr1）。结合连锁数据、肺肿瘤基因组改变和基因表达谱，将用于细化含有肺肿瘤耐药基因Ltr1和肺腺瘤耐药基因Par1的区域，后者已知与Pasf相互作用。候选基因将通过使用全基因组高密度BAG阵列分析肿瘤中的等位基因特异性遗传改变，以及基因表达微阵列来分析回交动物的正常组织和肿瘤。这些新模型和试剂的可用性将帮助我们解决与肺肿瘤易感性遗传基础相关的几个长期存在的问题。

DESCRIPTION (provided by applicant): Most human tumors arise from self-renewing cells of epithelial tissues. Tumors in the lung are the most deadly, with a projected 152,000 deaths in 2003 in the US alone. A strong genetic component contributes to lung cancer risk, as shown by evidence of familial clustering, and the fact that only 10-20% of smokers develop lung cancer. Identification of genetic variants that confer susceptibility to lung cancer will enable prediction of individual risk, and facilitate the development of novel therapeutic or preventive agents. A particular species of mouse (Mus spretus) is genetically resistant to development of lung cancer, due to the presence of germline polymorphisms that confer resistance. Crosses between sensitive and resistant mouse strains will be used in a genetic approach to identify lung tumor resistance genes. This analysis will be facilitated by the availability of an extensive database and tissue/tumor bank derived from a large backcross between the lung tumor-susceptible KrasM2 mice on the FVB background, with the resistant Mus spretus species. Data are already available both on the genomic changes associated with lung cancer initiation and progression, and on the genetic basis of lung cancer susceptibility. These data have implicated the Kras2 gene as a major determinant of lung tumor development and susceptibility. This particular ras gene family member is frequently mutated in both human and mouse lung tumors, and is one of the candidates for the major mouse lung tumor susceptibility locus Past. Two engineered mouse models will be used to test the role of Kras2 in lung tumor development and susceptibility. One involves a knock-in of a mutant Kras2 allele into the endogenous locus (/<rasM2 mice), resulting in 100% incidence of spontaneous lung tumors without carcinogen treatment. An additional model (HrasKI mice) involves a knock-in of the Hras 1 coding sequence into the Kras2 locus. Crosses between these strains and wild type mice of different genetic backgrounds will be used to analyze the requirement for Kras2 mutations in lung cancer, and to define the role of Kras2 in lung tumor susceptibility. Linkage analysis of lung tumor susceptibility has revealed the presence of several additional lung tumor resistance or susceptibility genes, including a locus on mouse chromosome 7 (Ltr1) that suppresses lung tumor formation in congenic mice. A combination of linkage data, genomic alterations in lung tumors, and gene expression profiles will be used to refine the regions containing the lung tumor resistance genes Ltr1 and the Pulmonary Adenoma Resistance gene Par1, which is known to interact with Pasf.Candidate genes will be selected by analysis of allele-specific genetic alterations in tumors using genome wide high-density BAG arrays, together with gene expression microarrays to profile both normal tissues and tumors from backcross animals. The availability of these novel models and reagents will help us to address several long standing questions related to the genetic basis of lung tumor susceptibility.