IDENTIFICATION OF GENES THAT MODIFY APC EXPRESSION

大肠腺瘤性息肉病（APC）基因是通过 在家族性APC患者中鉴定生殖系突变， 散发性结直肠癌患者的体细胞突变。 我们之前已经证明了两个大家族的存在， 一种减毒的APC称为AAPC。在AAPC家族中， 这种突变产生的结直肠息肉数量比 如果发生结肠直肠癌， AAPC家族的发病晚于APC。的标志特征 AAPC基因携带者是腺瘤性息肉数量变异较大者 在同一个家庭中观察。我们有兴趣测试 假设这种表型变异是由于基因修饰 APC基因的表达。已经确定了两个基因座， 小鼠APC表型（多发性肠肿瘤，MIN）。第一 基因座，EST-I，减少肠道肿瘤的数量和大小， 在Min小鼠中发育。其次，鼠甲基转移酶中的突变 基因也减弱Min表型。另外三个基因座 小鼠对药物诱导（非APC/MIN）肿瘤易感性 也被确认了。为了发现修饰基因， 我们的两个大的，特征良好的家庭，我们将使用遗传分析， 以鉴定修饰基因座。我们的主要分析方法将是 非参数连接（NPL）方法，不需要特定的 遗传模型我们将首先选择遗传标记的区域， 已知候选基因所在的基因组。如果这些区域中的任何一个 有证据表明有关联然后我们将寻找突变 在任何定位于细胞的候选基因的编码序列中， 关键区域。如果没有发现阳性或暗示性连锁结果， 这个最初的有限搜索，我们将进行一个完整的基因组范围内， 用一组300个高度多态性标记搜索修饰基因。 发现APC基因的一个或多个主要修饰基因座将有助于 在理解这一生物化学机制方面取得了重大进展， 重要的息肉产生基因。

The Adenomatous Polyposis Coli (APC) gene was discovered through the identification of germline mutations in patients with familial APC and somatic mutations in patients with sporadic cases of colorectal carcinoma. We previously have demonstrated the existence of two large families with an attenuated form of APC, called AAPC. In AAPC families, gene carriers of the mutation develop fewer numbers of colorectal polyps than do patients with classical APC and if colorectal cancer occurs, the average age of onset in AAPC families occurs later than in APC. A hallmark feature of AAPC gene carriers is the large variation in adenomatous polyp number observed within the same family. We are interested in testing the hypothesis that this variation in phenotype is due to genes that modify the expression of the APC gene. Two loci have been identified that modify the murine APC phenotype (multiple intestinal neoplasia, MIN). The first locus, MOM-1, reduces the number and size of intestinal neoplasias that develop in Min mice. Secondly, a mutations in the murine methyltransferase gene also attenuates the Min phenotype. Three additional loci that alter the susceptibility to drug-induced (non-APC/MIN) tumorigenesis in mice also have been identified. In an attempt to discover modifying gene(s) in our two large, well characterized families, we will use genetic analysis to identify modifying loci. Our primary method of analysis will be the non-parametric linkage (NPL) method that does not require a specific genetic model. We will initially choose genetic markers in regions of the genome where candidate genes are known to reside. If any of these regions show evidence for suggestive linkage. we will then search for mutations within coding sequences of any candidate genes that localized to the critical region. If no positive or suggestive linkage results are found in this initial limited search, we will then carry out a complete genome-wide search for a modifying gene with a set of 300 highly polymorphic markers. Discovery of one or more major modifying loci of the APC gene would a significant advance in understanding the biochemical mechanisms of this important polyp-producing gene.