MAPPING COLORECTAL CANCER SUSCEPTIBILITY LOCI

该提案的目标是识别和表征易感性 常见结直肠癌的基因位点。 为了完成这项任务，我们 将：1）确定和收集大大肠癌的DNA样本 基因组学，2）测试每个家族与候选区域的连锁， 结直肠癌易感基因座，3）进行基因组搜索， 结直肠癌易感基因座，4）创建精细结构图 5）确定敏感位点周围的特征， 遗传易感性携带者的异常表型。 的 用于遗传分析的犹他州人口的独特特征将 成为一项重要资产。 我们目前有最翔实的一套 乳腺癌基因组中的激酶（LOD评分） 流行病学社区。 我们也有最翔实的一套 黑色素瘤易感性激酶，它确定了9 p黑色素瘤 易感性基因座（Cannon-Albright等，1992年）。 我们会查明 大犹他州的亲属可能携带结直肠癌的易感性 基因座，并研究那些不与2号染色体连锁的激酶 或先前鉴定的5号染色体基因座。 这些犹他州的亲戚们 与我们约翰霍普金斯大学的未映射的运动学相结合 (JHU)合作者 首先将分析所有运动学的关联性 与候选基因座和已知基因（APC，2号染色体HNPCC，p53，DCC 和ras）。 然后，在基因组连锁搜索中，它们将被筛选， 一系列短串联重复标记（STR）。 当一个新的结直肠癌 癌症易感位点已确定，我们将确定关键 重组在这些大的激酶，并使用它们来创造良好的 磁化率位点周围的结构图。 新的STR标记将 来帮助这一努力。 单倍型将围绕 一个易感位点来识别基因携带者。 我们将描述 每种鉴定的结直肠癌易感性的表型效应 基因座 这是一个跨学科的三个提案之一， 一个致力于了解 通过遗传流行病学方法研究结直肠癌的病因学。 我们的建议最好用统一的主题来描述， 结肠癌基因的鉴定。“另外两项建议将 研究遗传性结直肠癌的遗传流行病学（G. Petersen，P.I.）。以及饮食和遗传改变 （S.汉密尔顿，P.I.）。 遗传流行病学提供了一个研究框架 这些问题在家庭和人口，并制定新的 分析这些数据的方法。

The goal of this proposal is to identify and characterize susceptibility loci for common colorectal cancer. In order to accomplish this task we will: 1) ascertain and collect DNA samples from large colorectal cancer kindreds, 2) test each kindred for linkage to candidate regions for colorectal cancer susceptibility loci, 3) perform a genomic search for colorectal cancer susceptibility loci, 4) create a fine structure map around the susceptibility loci identified, and 5) characterize the abnormal phenotype in carriers of the inherited susceptibility. The unique characteristics of the Utah population for genetic analysis will be an essential asset. We currently have the most informative set of breast cancer kindreds (in terms of LOD score) in the genetic epidemiology community. We also have the most informative set of melanoma susceptibility kindreds, which identified the 9p melanoma susceptibility locus (Cannon-Albright et al., 1992). We will ascertain large Utah kindreds likely to carry colorectal cancer susceptibility loci, and study those kindreds which are not linked to the chromosome 2 or chromosome 5 loci previously identified. These Utah kindreds will be pooled with unmapped kindreds available from our Johns Hopkins University (JHU) collaborators. All kindreds will be analyzed for linkage first with candidate loci and known genes (APC, chromosome 2 HNPCC, p53, DCC and ras). Then, in a genomic linkage search, they will be screened with a series of short tandem repeat markers (STRs). When a new colorectal cancer susceptibility locus is identified, we will identify key recombinants in these large kindreds and use them to create fine structure map around the susceptibility locus. New STR markers will be developed to aid in this effort. Haplotypes will be constructed around a susceptibility locus to identify gene carriers. We will characterize the phenotypic effect of each identified colorectal cancer susceptibility locus. This proposal is one of three submitted by an interdisciplinary collaborative group of investigators committed to understanding the etiology of colorectal cancer through genetic epidemiologic approaches. Our proposals are best described by the unifying theme, "Beyond identification of colon cancer genes." The other two proposals will examine the genetic epidemiology of the hereditary colorectal cancers (G. Petersen, P.I.). and diet and genetic alterations in colorectal neoplasia (S. Hamilton, P.I.). Genetic epidemiology provides a framework to study these questions in families and populations, and to develop new methodologies for analyzing these data.