Genetic interactions in colorectal cancer susceptibility

描述(申请人提供)：大约30%的结直肠癌患者因遗传因素而患上S。在小鼠模型中，上位性效应(只有在存在第二个遗传变异时才能观察到的风险)和协同效应(遗传变异之间的乘法效应)已被证明是癌症风险的重要决定因素。由于存在大量可能的组合，使用全基因组关联研究中的基因类型来鉴定上位性和协同性相互作用是困难的。我们提出了一种以人类基因组中的区域为目标进行遗传相互作用分析的老鼠-人类策略，以降低这些研究的复杂性。来自人类病例/对照研究的数据显示，AURKA和PTPRJ两个基因的变异会增加结直肠癌的风险。在小鼠中，这两个基因都映射到与其他基因座相互作用的基因座(遗传区)，从而协同增加癌症风险。这项建议的目标是确定与AURKA和PTPRJ相互作用的易感变异，以增加结直肠癌风险。我们假设人类等同于小鼠结直肠癌易感基因的基因座将与AURKA和PTPRJ相互作用。为了验证这一假说并确定结直肠癌风险的相互作用的遗传变异，我们将：1.测试AURKA和PTPRJ相互作用基因座的编码和调节区的变异，以寻找肿瘤中的变异特异性变化。以往的研究表明，在肿瘤中，癌症易感性变异优先获得，而癌症耐药变异优先丢失，从而为识别这些变异提供了工具。使用来自600个个体的匹配的正常和结直肠癌DNA，映射到候选AURKA和PTPRJ相互作用基因的变异将被评估变异特异性的收益或损失。2.对从小鼠模型中识别的相互作用的CRC基因座进行双向交互作用研究。将使用2200例结直肠癌病例和对照的已公布的全基因组关联数据，测试映射到四个相互作用的小鼠易感基因座的人类等值区域的变体在人类中的遗传交互作用。AIMS 1和AIMS 2的重大发现将通过对用于定位易感基因的小鼠品系的序列和基因表达研究来验证。显示癌症风险证据的变异将是未来基于人群的病例对照研究和机制研究的重点。这项工作将导致识别增加儿童结核病风险的相互作用的遗传变异，并将产生更好的儿童疾病风险评估工具。由于结直肠癌的癌症死亡率可以通过在结肠镜检查中去除前体息肉来显著降低，识别高危个体将降低这种疾病的发病率和死亡率。从这些研究中发现的基因和途径将为结直肠癌的治疗提供新的治疗靶点。 公共卫生相关性：这项工作有可能确定共同作用的基因变异组合，以增加结直肠癌的易感性。识别这些变异将导致更好的结直肠癌风险评估，更全面地了解结直肠癌的发生机制和新的治疗靶点。

DESCRIPTION (provided by applicant): Approximately 30% of colorectal cancer (CRC) risk s due to genetic (inherited) factors. Using mouse models, epistatic effects (risks observed only in the presence of a second genetic variant) and synergistic effects (multiplicative effects between genetic variants) have been shown to be important determinants of cancer risk. Identification of epistatic and synergistic interactions using genotypes from whole genome association studies is difficult due to the large number of possible combinations. We propose a mouse- human strategy to target regions in the human genome for genetic interaction analyses to reduce the complexity of these studies. Data from human case/control studies show that variants in two genes, AURKA and PTPRJ, increase CRC risk. In the mouse, both genes map to loci (genetic regions) that interact with other loci to synergistically increase cancer risk. The goal of this proposal is to identify susceptibility variants that interact with AURKA and PTPRJ to increase CRC risk. We hypothesize that the human equivalent loci to mouse CRC susceptibility loci will interact with AURKA and PTPRJ. To test this hypothesis and to identify interacting genetic variants for CRC risk we will: 1. Test variants from coding and regulatory regions of AURKA- and PTPRJ-interacting loci for variant specific changes in tumors. Previous studies show that cancer susceptibility variants are preferentially gained and cancer resistance variants are preferentially lost in tumors, thus providing a tool to identify these variants. Using matched normal and CRC tumor DNA from 600 individuals, variants that map to candidate AURKA and PTPRJ- interacting loci will be assessed for variant specific gains or losses. 2. Conduct two-way interaction studies of interacting CRC loci identified from mouse models. Variants that map to human equivalent regions of four interacting mouse susceptibility loci will be tested for genetic interactions in humans using published whole genome association data from 2200 CRC cases and controls. Significant findings from Aims 1 and 2 will be validated by sequence and gene expression studies in the strains of mice used to map the susceptibility loci. Variants showing evidence of cancer risk will be the focus of future population-based case control studies and mechanistic studies. This work will lead to the identification of interacting genetic variants which increase CRC risk and will result in better risk assessment tools for CRC. Since cancer mortality for CRC can be significantly reduced by the removal of precursor polyps during screening colonoscopy, identification of at risk individuals will decrease the incidence and mortality of this disease. Genes and pathways identified from these studies will provide new therapeutic targets for CRC treatment. PUBLIC HEALTH RELEVANCE: This work has the potential to identify combinations of genetic variants that work together to increase susceptibility to colorectal cancer. Identification of these variants will lead to better risk assessments for colorectal cancer, a more complete understanding of the mechanisms of colorectal tumorigenesis and new therapeutic targets.