Effect of cooperating mutations and genetic background on colon cancer metastasis

描述(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，死亡几乎完全归因于转移性肝病。因此，了解原发肿瘤如何生长并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，但对影响结直肠癌的具体遗传因素知之甚少。这项拟议的研究将开发一种结直肠癌的小鼠模型，该模型将允许研究遗传背景是否通过与特定的转化突变相互作用来影响肿瘤的发展、进展和转移。肿瘤生长、组织病理学分析和基因表达分析将被用来表征新模型中的癌症发展，并将其与现有的利用不同肿瘤启动事件的CRC小鼠模型进行比较。类似的分析将在具有不同母体基因型别和协同突变的小鼠身上进行，以调查突变和遗传背景如何相互作用影响肿瘤进展。这项研究的长期目标是能够预测哪些患者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。 公共卫生相关性：在发达国家，结直肠癌是与癌症相关的死亡的第二大原因，死亡几乎完全归因于癌细胞向身体其他部位的扩散(即转移)。了解影响结直肠癌转移的遗传因素将有助于识别预计具有较高转移疾病风险的患者，并可能对这些患者的干预策略产生重大影响。

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. PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer-related deaths in developed countries, with mortality almost exclusively attributed to dissemination of cancer cells to other parts of the body (i.e. metastasis). Understanding the genetic factors that influence colorectal cancer metastasis will aid in identifying patients predicted to have a higher risk of metastatic disease and could have a significant impact on intervention strategies for these patients.