Transposon-based screens for colorectal cancer genes

描述（由申请人提供）：结直肠癌（CRC）的发展是一种严重和可怕的恶性肿瘤，是美国癌症相关死亡的第二大原因。关于早期结直肠癌是如何发展的，我们知道很多，但关于这种疾病的进展，我们还需要了解很多。显然，发现导致结直肠癌进展（如转移）的基因和遗传途径是可取的。可用于检测结直肠癌和预测肿瘤进展（侵袭/转移）的生物标志物在结直肠癌高危患者的临床管理中是迫切需要的，例如过去切除过息肉的患者。这个项目可以帮助解决国家癌症研究所计划创建一个全面的人类癌症基因组图谱的任务。虽然对结直肠癌中可能发生的体细胞变化已经有了一些了解，但很可能还有很多东西有待了解。对可能导致CRC或在特定已知人类CRC突变启动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，必将指导未来的治疗。这项资助的主要目标是使用一种新的随机、睡美人（SB）转座子为基础的体细胞插入突变系统来模拟CRC。Largaespada。Largaespada博士和Cormier博士已经建立了用SB转座子载体转位诱导结直肠癌的方法。候选CRC基因将通过小鼠转基因和其他实验来测试其致癌能力。研究结果还将与人类结直肠癌的基因改变进行比较。相关性：本项目旨在确定哪些基因在胃肠道上皮细胞中发生改变时导致结直肠癌。了解导致结直肠癌的基因是至关重要的，这样才能开发出有效的治疗方法。将建立一个小鼠CRC模型，其中所有导致CRC的突变基因都可以被识别出来。然后，这些基因的一个子集将被仔细分析，以确定它们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进行的研究，以了解结直肠癌的发展过程。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.