Use of Closely Related Inbred Strains to Identify Modifier Loci of Tumorigenesis

描述（由申请人提供）：对影响癌症易感性或抗性的基因的探索一直是科学界的一项重大任务。在美国，每年有成千上万的人受到小肠和结肠直肠癌（CRC）的影响。虽然环境因素在疾病病因学中起作用，但在风险评估和开发预防措施和新的治疗方法时，揭示潜在的遗传因素是必不可少的。家族性腺瘤性息肉病（FAP）是一种遗传性疾病，易使个体在肠道中形成息肉，并最终导致癌症，其中腺瘤性息肉病（APC）肿瘤抑制基因发生突变。小鼠模型已成为研究肿瘤发生过程的重要工具。携带APC基因（ApcMin）小鼠同源物突变的小鼠的遗传背景对肿瘤表型的表现至关重要，因为近交系对息肉病的易感性各不相同。虽然复杂的性状分析已经确定了基因座，修改肠道肿瘤的数量和大小，乳腺肿瘤的发展，辐射诱导的腺瘤的多样性在ApcMin/+小鼠，不到少数的基因已被确定的日期。有人认为，多位点相互作用可能是修饰基因难以找到的原因之一。为了检测到表型的转变，可能必须同时改变途径中的几个基因。我们选择采用一种不仅能解释单基因座效应，而且能解释多基因座遗传影响的表型的方法。与利用小鼠品系之间多样性的传统数量性状基因座（QTL）研究不同，我们将利用密切相关的近交系之间的遗传相似性来证明这种替代方法在发现影响肿瘤表型的基因方面的有用性。我们最近发现，来自C57 BL/6 J（B6）和密切相关的菌株之间的杂交的F1 ApcMin/+后代与它们的B6亲本相比，对发展息肉的易感性显著改变。我们将使用经典遗传学，分子工具和计算资源的组合，以确定调节肠道肿瘤发生的生物分子途径。我们的目标不仅是确定新的修饰基因座，而且要牢固地建立这种替代方法，以优化复杂的性状筛选，并加快鉴定影响肿瘤发生易感性或抗性的致病基因的过程。 公共卫生相关性：一种形式的基因可以使一个人对癌症易感，而同一基因的另一种形式可以使另一个人对威胁生命的癌症具有抵抗力。这项研究旨在发现具有保护小肠和结肠肿瘤发展功能的基因。第二个目标是建立快速有效地鉴定这些基因和途径的方法。有了这些知识，研究可以为有风险的人开发新的预防选择，并为癌症患者开发潜在的治疗选择。

DESCRIPTION (provided by applicant): The quest for genes influencing susceptibility or resistance to cancer has been a major undertaking by the scientific community. Every year tens of thousands of individuals in the United States are affected by small intestine and colorectal cancers (CRC). Although environmental factors play a role in disease etiology, uncovering underlying genetic factors is imperative in risk assessment and for developing preventative measures and novel therapeutics for treatment. The adenomatous polyposis coli (APC) tumor suppressor gene is mutated in Familial Adenomatous Polyposis (FAP), an inherited disorder that predisposes individuals to developing polyps in their intestinal tract and which eventually leads to cancer. Mouse models have served as valuable tools to study the process of tumorigenesis. The genetic background of mice carrying a mutation in the murine homolog of the APC gene (ApcMin) is critical to the manifestation of tumor phenotypes, as inbred strains vary in their susceptibility to polyposis. Although complex trait analyses have identified loci tha modify intestinal tumor number and size, mammary tumor development, and radiation-induced adenoma multiplicity in ApcMin/+ mice, less than a handful of genes have been identified to date. It has been suggested that multiple-locus interactions may be one reason that modifier genes are difficult to find. Several genes in a pathway may have to be altered concurrently in order for a shift in phenotype to be detected. We chose to adopt an approach that will account for not only single-locus effects, but phenotypes influenced by multiple-loci inheritance as well. Unlike traditional quantitative trait loci (QTL) studies that exploit the diversity among mouse strains, we will take advantage of genetic similarities between closely-related inbred strains to demonstrate the usefulness of this alternative approach to discover genes that influence tumor phenotypes. We recently found that F1 ApcMin/+ offspring from crosses between C57BL/6J (B6) and closely-related strains have significantly altered susceptibilities to developing polyps than their B6 parents. We will use a combination of classical genetics, molecular tools, and computational resources to identify biomolecular pathways that modulate intestinal tumorigenesis. Our goal is not only to identify new modifier loci, but also to firmly establish thi alternative approach to optimize complex trait screens and speed the process of identification of causative genes influencing susceptibility or resistance to tumorigenesis. PUBLIC HEALTH RELEVANCE: One form of a gene can make a person susceptible to cancer, while another form of the same gene can make another person resistant to a life-threatening cancer. This research is designed to discover genes that function to protect against the development of tumors in the small intestine and colon. A second goal is to establish methods to quickly and efficiently identify these genes and pathways. With this knowledge, research can move towards developing novel preventative options for people at risk and potential therapeutic options for patients with cancer.