Susceptibility Genes and Colorectal Cancer

描述(由申请人提供)：对影响癌症易感性的基因的研究是一个快速发展的领域。这项建议的重点是识别和表征影响胃肠道癌症发展的新的修饰基因。我们选择的系统涉及肿瘤抑制基因，腺瘤性息肉病结肠(APC)。APC基因突变会导致遗传性和散发性结直肠癌。ApcMin小鼠的APC基因同源物发生突变，并在其整个小肠和大肠发展为多发性腺瘤。QTL研究确定了一个基因座，Min(Most1)的修饰物，它显著改变了ApcMin诱导的肿瘤数量和大小。我们和其他人已经报道了分泌型II型磷脂酶A2(Pla2g2a)基因至少与MOM1表型的一部分有关。虽然很明显存在其他修饰基因座，但由于MOM1基因座在这些杂交组合中的分离，它们无法被识别。为了进一步剖析遗传修饰的途径，我们通过交换C57BL6/J和C3H/HeJ小鼠之间的Mom1区域构建了互易的同源品系。这些菌株导致通常易感的B6小鼠含有抗药性Mom1等位基因，类似地，抗药性的C3H鼠含有易感的MOM1基因。QTL分析揭示了5个新的修饰区域的存在。我们建议分离和鉴定B6-C3H相互同源菌株之间最有效的修饰物。我们将开发同源基因资源来研究新的妈妈#基因座的作用。此外，我们将细化每个妈妈#基因座的遗传位置，使用位置和候选基因方法来确定负责妈妈#表型的基因(S)。最后，我们将进行几项生物检测，以进一步了解MOMA#功能的分子机制。本文概述的研究将最终深入了解这些修饰基因在肿瘤预防和治疗反应中的预测价值，并为新的化学预防药物提供途径。我们相信“一盎司的预防胜过一磅的治疗”。我们的研究旨在寻找可以预测哪些人有患结直肠癌风险的因素。通过研究这些因素，我们希望能够开发出新的方法，从一开始就帮助预防癌症的发展。

DESCRIPTION (provided by applicant): The study of genes that influence cancer susceptibility is a rapidly evolving field. This proposal is focused on identifying and characterizing novel modifier loci that influence the development of cancer in the gastrointestinal tract. The system we have chosen involves the tumor suppressor gene, Adenomatous Polyposis Coli (APC). Mutations in APC cause inherited and sporadic colorectal cancers. ApcMin mice have a mutation in the homologue of the APC gene and develop multiple adenomas throughout their small and large intestines. QTL studies identified a locus, Modifier of Min (Mom 1), that dramatically modifies ApcMin-induced tumor number and size. We and others have reported that the secretory type II Phospholipase A2 (Pla2g2a) gene is responsible for at least a part of the Mom1 phenotype. While it was clear that other modifier loci are present, they were unable to be identified due to segregation of the Mom1 locus in these crosses. To further dissect genetic modifier pathways, we constructed reciprocal congenic strains by exchanging the Mom1 region between C57BL6/J and C3H/HeJ mice. These strains resulted in the usually susceptible B6 mice containinga resistant Mom1 allele and similarly, the resistant C3H mice containing a susceptible Mom1 locus. QTL analysis has now revealed the presence of 5 novel modifier regions. We propose to isolate and characterize the most potent modifiers identified between the B6-C3H reciprocal congenic strains. We will develop congenic resources to study the action of the new Mom# loci. In addition, we will refine the genetic location of each Mom# locus, using positional and candidate gene approaches to identify the gene(s) responsible for Mom# phenotypes. Finally, we will perform several biological assays to gain further insight into the molecular mechanisms underlying Mom# function. The studies outlined here will ultimately lead to insights regarding the predictive value of these modifier genes in tumor prevention and response to treatment, as well as provide avenues for novel chemopreventive agents. We believe that "an ounce of prevention is worth a pound of cure". Our research is designed to find factors that can predict which people are at-risk for developing colorectal cancer. By studying these factors, we hope to be able to develop new ways to help prevent cancers from developing in the first place.