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

描述（由申请人提供）：寻找影响癌症易感性或抗性的基因一直是科学界的一项主要工作。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中起作用，但发现潜在的遗传因素对于风险评估和制定预防措施和新的治疗方法至关重要。家族性腺瘤性息肉病（FAP）是一种遗传性疾病，易使个体在肠道内发生息肉，并最终导致癌症，大肠腺瘤性息肉病（APC）肿瘤抑制基因在FAP中发生突变。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）小鼠同源基因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不同。虽然复杂的性状分析已经确定了在ApcMin/+小鼠中改变肠道肿瘤数量和大小、乳腺肿瘤发展和辐射诱导的腺瘤多样性的位点，但迄今为止已经确定的基因还不到少数。有人认为，多位点相互作用可能是难以找到修饰基因的原因之一。为了检测到表型的变化，可能必须同时改变途径中的几个基因。我们选择采用一种方法，不仅可以解释单位点效应，还可以解释受多位点遗传影响的表型。与利用小鼠品系之间多样性的传统数量性状位点（QTL）研究不同，我们将利用近亲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效性。我们最近发现，与B6亲本相比，C57BL/6J （B6）与近亲杂交的F1 ApcMin/+后代对息肉的易感性显著改变。我们将结合经典遗传学，分子工具和计算资源来确定调节肠道肿瘤发生的生物分子途径。我们的目标不仅是鉴定新的修饰位点，而且要牢固地建立这种替代方法来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。

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.