Systems genetics analysis of tumor evolution in the mouse

摘要 小鼠肿瘤进化的系统遗传学分析。 转移是人类癌症死亡的主要原因，但许多因素在决定癌症死亡方面发挥作用。 初始化细胞到达该结束阶段所采取的路线。我们知道肿瘤的产生是由于 遗传因素和环境暴露的影响，并采取了长远的观点， 在小鼠中成功建立人类癌症模型需要我们考虑到 基因和环境。本研究的最终目标是建立一个完整的系统遗传学 从细胞、信号通路和参与转移的特定基因突变的角度， 单启动细胞，使用皮肤多阶段致癌作用的最佳表征模型之一。 基于过去15年来NCI MMHCC的主要资助，我们建立了一种独特的组织， 肿瘤库包括来自遗传学上的数千个Ras突变鳞状肿瘤样本， 异种小鼠群体。这些样品包括从良性病变到转移的所有阶段， 特别是包括数百个匹配的原发癌和来自同一原发癌的远处转移癌 动物所有肿瘤均通过暴露于诱变剂和肿瘤促进剂诱导，导致复杂的 在突变频率和类型上类似于人类鳞状细胞癌基因组图谱的基因组景观 皮肤癌、头颈癌和肺癌。队列中的所有小鼠都已进行全基因组基因分型， 促进连锁和eQTL分析，以确定启动，良性肿瘤形成， 进展和转移性播散。该项目将利用这一独特的组织库和数据库， 使用基因组技术，以及新的小鼠品系，以确定良性和 恶性肿瘤、恶性进展风险的生物标志物和转移的遗传驱动因素。 计算网络分析工具将用于研究信号通路的演变，例如 Ras通路，通过多个阶段的致癌作用，以确定这些网络的变化，将确定 潜在的新型癌症靶基因。最后，我们将启动一系列新的翻译研究， 免疫疗法，基于我们观察到这些化学诱导的肿瘤具有新的新抗原 并显示出对免疫检查点蛋白抑制剂的有希望的应答。

Abstract Systems Genetics Analysis of Tumor Evolution in the Mouse. Metastasis is the major cause of death due to cancer in humans, but many factors play a role in determining the route taken by initiated cells to reach this end stage. We know that tumors arise due to the combined effects of inherited genetic factors and environmental exposures, and have taken the long term view that successful modeling of human cancer in the mouse requires us to take account of interactions between genetics and environment. The over-arching goal of this research is to develop an integrated systems genetics view of the cells, signaling pathways and mutations in specific genes involved in evolution of metastasis from single initiated cells, using one of the best characterized models of multistage carcinogenesis of the skin. Based on major funding from the NCI MMHCC over the past 15 years, we have built up a unique tissue and tumor bank comprising thousands of samples of Ras-mutant squamous tumors from a genetically heterogeneous mouse population. These samples encompass all stages from benign lesions to metastases, and in particular include hundreds of matched primary carcinomas and distant metastases from the same animals. All tumors were induced by exposure to mutagens and tumor promoting agents, resulting in complex genomic landscapes that resemble, in mutation frequency and type, the genomic profiles of human squamous carcinomas of the skin, head and neck, and lung. All mice in the cohort have been genotyped genome-wide to facilitate linkage and eQTL analysis to identify genetic determinants of initiation, benign tumor formation, progression and metastatic dissemination. This project will exploit this unique tissue bank and database by using genomic technologies, together with novel mouse strains, to identify the cells of origin of benign and malignant tumors, biomarkers of risk of malignant progression, and genetic drivers of metastasis. Computational network analysis tools will be used to study the evolution of signaling pathways, for example the Ras pathway, through multiple stages of carcinogenesis, to identify changes in these networks that will identify potential novel cancer target genes. Finally we will initiate a new series of translational studies of immunotherapy, based on our observation that these chemically induced tumors harbor novel neo-antigens and show promising responses to inhibitors of immune checkpoint proteins.