Effect of cooperating mutations and genetic background on colon cancer metastasis

描述（由申请人提供）：结直肠癌（CRC）是美国癌症相关死亡的第二大原因，死亡率几乎完全归因于转移性肝病。因此，了解原发性肿瘤如何生长和扩散到继发部位的机制具有重要的临床意义。越来越多的证据表明遗传背景是转移易感性的重要决定因素，但对影响CRC的特定遗传因素知之甚少。拟议的研究将开发一种CRC小鼠模型，该模型将允许调查遗传背景是否通过与特定转化突变的相互作用影响肿瘤的发展，进展和转移。肿瘤生长、组织病理学分析和基因表达分析将用于表征新模型中的癌症发展，并将其与利用不同肿瘤起始事件的现有CRC小鼠模型进行比较。将对具有不同母体基因型和协同突变的小鼠进行类似分析，以研究突变和遗传背景如何相互作用以影响肿瘤进展。这项研究的长期目标是能够预测哪些患者具有更高的转移性疾病风险，并为这些患者制定更合适的治疗策略。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States, with mortality almost exclusively attributed to metastatic liver disease. Therefore, understanding the mechanisms governing how a primary tumor grows and disseminates to secondary sites is of great clinical importance. There is increasing evidence suggesting that genetic background is an important determinant of metastatic susceptibility, but little is known about the specific genetic factors that affect CRC. The proposed research will develop a mouse model of CRC that will allow the investigation of whether genetic background influences tumor development, progression, and metastases through interaction with specific transforming mutations. Tumor growth, histopathological analysis, and gene expression analysis will be used to characterize cancer development in the new model and compare it to an existing CRC mouse model that utilizes a different tumor initiating event. Similar analyses will be performed on mice with differing maternal genotypes and cooperating mutations to investigate how the mutations and genetic background interact to influence tumor progression. The long-term goal of this research is to be able to predict which patients have a higher risk of metastatic disease and develop more appropriate therapeutic strategies for these individuals.