Transposon-based screens for colorectal cancer genes

描述（由申请人提供）：结直肠癌（CRC）的发展是一种严重且令人担忧的恶性肿瘤，是美国癌症相关死亡的第二大原因。关于CRC在早期阶段如何发展已经知道很多，但关于这种疾病的进展还有很多需要了解。显然，希望发现导致CRC进展如转移的基因和遗传途径。可用于检测CRC和预测肿瘤进展（侵袭/转移）的生物标志物在CRC高风险患者的临床管理中迫切需要-例如过去切除息肉的患者。这个项目可以帮助解决国家癌症研究所计划的使命，即创建一个全面的人类癌症基因组图谱。虽然在CRC中可能发生的体细胞变化方面已经获得了一些见解，但可能还有很多东西需要学习。对可能导致CRC或在由特定的已知人类CRC突变引发后加速恶性肿瘤的体细胞突变进行无偏筛选将是非常宝贵的。CRC癌症基因的鉴定以及这些突变在个体病例中发生的模式肯定会指导未来的治疗。这项资助的主要目标是使用Largaespada博士开发的随机、基于睡美人（SB）转座子的体细胞插入诱变的新系统来模拟CRC。通过SB转座子载体的转座来诱导CRC的方法已经由Largaespada博士和Corp.博士建立。候选CRC基因将通过小鼠转基因和其他检测来测试其致癌能力。还将结果与人类CRC遗传改变进行比较。相关性：该项目旨在确定哪些基因在胃肠道上皮细胞中发生改变时会导致CRC。了解哪些基因导致CRC至关重要，以便开发针对这种癌症的有效疗法。将创建CRC的小鼠模型，其中可以鉴定导致CRC的所有突变基因。然后将仔细分析这些基因的子集在细胞和小鼠模型中的个体效应。公共卫生相关性：该提案描述了在小鼠中所做的工作，以了解结直肠癌如何发展。我们将发现哪些基因在受损时会导致这些肿瘤。这将帮助我们决定如何最好地治疗这种非常常见且往往致命的疾病。

DESCRIPTION (provided by applicant): The development of colorectal cancer (CRC) is a serious and feared malignancy, and the second leading cause of cancer-related death in the United States. Much is known about how CRC develops at early stages, but much remains to be learned about progression of this disease. Clearly it would be desirable to discover the genes and genetic pathways that lead to CRC progression such as metastases. Biomarkers that could be used to detect CRC and to predict tumor progression (invasion/metastasis) are desperately needed in the clinical management of patients at high risk for CRC - such as patients who've had polyps removed in the past. This project can help to address the mission of the National Cancer Institute's plan to create a comprehensive human cancer genome atlas. While some insight has been gained in the somatic changes that can occur in CRC, it is likely that much remains to be learned. An unbiased screen for somatic mutations that could cause CRC or accelerate malignancy after initiation by specific known human CRC mutations would be invaluable. The identification of CRC cancer genes, and the patterns in which these mutations occur in individual cases, will certainly guide future therapies. It is the main goal of this grant to model CRC using a novel system for random, Sleeping Beauty (SB) transposon-based, somatic insertional mutagenesis developed by Drs. Largaespada. Methods to induce CRC by transposition of SB transposon vectors in have already been established by Dr. Largaespada and Dr. Cormier. Candidate CRC genes will be tested for their ability to cause cancer by mouse transgenesis and other assays. The results will also be compared to human CRC genetic alterations. Relevance: This project seeks to define what genes, when altered in GI tract epithelial cells, cause CRC. It is critical to know what genes cause CRC so that effective therapies for this cancer can be developed. A mouse model of CRC will be created in which all the mutated genes that cause the CRC can be identified. Then a subset of these genes will be analyzed carefully for their individual effects in cell and mouse models. PUBLIC HEALTH RELEVANCE: This proposal describes work done in mice to understand how colorectal cancer develops. We will discover what genes, when damaged, can cause these tumors. This will help us decide how best to treat this very common and often lethal disease.