Genetic interactions in colorectal cancer susceptibility

摘要 大约30%的结直肠癌(CRC)风险是由遗传因素引起的。使用鼠标 模型、上位性效应(仅在存在第二个遗传变异时观察到的风险)和协同效应 效应(遗传变异之间的乘法效应)已被证明是 癌症风险。利用全基因组的基因型别鉴定上位性和协同性互作 由于可能的组合数量众多，关联研究很困难。我们提出了一种老鼠- 人类以人类基因组中的区域为目标进行遗传相互作用分析的策略 这些研究的复杂性。来自人类病例/对照研究的数据显示，两个基因的变异， AURKA和PTPRJ增加了结直肠癌的风险。在小鼠中，这两个基因都映射到 与其他基因座相互作用，协同增加癌症风险。这项提案的目标是确定 与AURKA和PTPRJ相互作用增加结直肠癌风险的易感变异。我们假设 人类等同于小鼠结直肠癌易感基因座将与AURKA和PTPRJ相互作用。为了测试这一点 假设和确定CRC风险的相互作用的遗传变异，我们将：1.从编码中测试变异 以及AURKA和PTPRJ相互作用基因的调节区，用于肿瘤中不同的特异性变化。 以前的研究表明，癌症易感变异体优先获得和抗癌 变异体在肿瘤中优先丢失，因此提供了一种工具来识别这些变异体。使用匹配 来自600名个体的正常和结直肠癌DNA，映射到候选AURKA和PTPRJ的变体- 相互作用的轨迹将被评估为不同的具体收益或损失。2.开展双向互动研究 从小鼠模型中识别出的相互作用的CRC基因座。映射到人类等同区域的变体 四个相互作用的小鼠易感基因座将用于测试人类的遗传交互作用 2200例结直肠癌患者和对照的全基因组关联数据。AIMS 1和AIMS的重要发现 2将通过序列和基因表达研究在用于定位该基因的小鼠品系中得到验证 易感基因座。显示癌症风险证据的变异将是未来基于人群的研究的重点 病例对照研究和机制研究。这项工作将导致互作基因的鉴定 增加儿童权利公约风险的变种，并将产生更好的儿童权利公约风险评估工具。自患癌症以来 在筛查过程中清除前驱息肉可显著降低结直肠癌的死亡率 结肠镜检查，识别高危人群，可降低本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。

Summary Approximately 30% of colorectal cancer (CRC) risk is 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.