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

描述(申请人提供)：寻找影响癌症易感性或抗药性的基因一直是科学界的一项主要任务。在美国，每年有数以万计的人受到小肠和结直肠癌(CRC)的影响。虽然环境因素在疾病病因学中发挥作用，但在风险评估和开发预防措施和治疗新疗法方面，发现潜在的遗传因素是当务之急。家族性腺瘤性息肉病(FAP)是一种遗传性疾病，易导致肠道息肉发展，最终导致癌症。小鼠模型已成为研究肿瘤发生过程的宝贵工具。携带APC基因同源突变(ApcMin)的小鼠的遗传背景对肿瘤表型的表现至关重要，因为近交系小鼠对息肉病的易感性不同。尽管复杂的性状分析已经确定了影响ApcMin/+小鼠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基因，但到目前为止还没有发现几个基因。有人认为，多位点的相互作用可能是修饰基因难以找到的原因之一。一条途径中的几个基因可能必须同时改变，才能检测到表型的变化。我们选择采用一种方法，不仅要考虑单基因座效应，还要考虑受多基因座遗传影响的表型。与传统的利用小鼠品系间多样性的数量性状座位(QTL)研究不同，我们将利用近亲交配品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，C57BL/6J(B6)与近缘品系杂交产生的F1 ApcMin/+后代与其亲本相比，显著改变了发生息肉的易感性。我们将使用经典遗传学、分子工具和计算资源的组合来识别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，而且牢固地建立这一替代方法，以优化复杂的性状筛选，并加快识别影响肿瘤发生易感性或耐药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.