IDENTIFICATION OF GENES THAT MODIFY APC EXPRESSION

腺瘤性息肉病结肠(APC)基因是通过 家族性APC和APC患者胚系突变的鉴定 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 APC的一种衰减形式，称为AAPC。在AAPC家族中，基因携带者 这种突变导致的大肠息肉的数量比患者少 对于典型的APC，如果发生结直肠癌，平均年龄 AAPC家系发病晚于APC。的一个标志性特征 AAPC基因携带者是腺瘤性息肉数量变异较大的人群 在同一个家庭中观察到的。我们有兴趣测试 假设表型的这种变化是由于基因改变 APC基因的表达。已经确定了两个修改的基因座 小鼠APC表型(多发性肠道肿瘤，MIN)。第一 MOM-1基因座可以减少肠道肿瘤的数量和大小 在Min小鼠体内发育。其次，小鼠甲基转移酶的a突变 基因还减弱了Min表型。另外三个改变的基因座 小鼠对药物诱导(非APC/min)致瘤的敏感性 也已被确认。在发现修饰基因(S)中的尝试 我们这两个特征良好的大家庭，我们将使用基因分析 以确定修饰的基因座。我们的主要分析方法将是 非参数链接(NPL)方法，不需要特定的 遗传模型。我们将首先选择遗传标记在 已知候选基因所在的基因组。如果这些地区中的任何一个 展示暗示联系的证据。然后我们将搜索突变 在定位于该基因的任何候选基因的编码序列内 临界区。如果没有发现阳性或提示的链接结果 最初的有限搜索，然后我们将进行完整的全基因组 寻找具有300个高度多态标记的修饰基因。 发现APC基因的一个或多个主要修饰位点将是一种 在理解这一生化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.