Susceptibility Genes and Colorectal Cancer

易感基因与结直肠癌

• 批准号: 7848844
• 负责人: Linda D Siracusa
• 金额: $ 29.45万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848844
• 关键词: APC gene; Adenomatous Polyposis Coli; Affect; Alleles; Backcrossings; Biological Assay; Biological Models; C3H/HeJ Mouse; Candidate Disease Gene; Chemopreventive Agent; Chromosomes, Human, Pair 5; Code; Colorectal Cancer; Congenic Strain; DNA Sequence; Development; Gastrointestinal tract structure; Gene Targeting; Gene-Modified; Generations; Genes; Genetic; Genome; Goals; Growth; Homologous Gene; Human; Inbred C3H Mice; Inbred Strain; Inherited; Intestines; Investigation; Large Intestine; Lead; Location; Malignant Neoplasms; Modeling; Molecular; Molecular Analysis; Molecular Profiling; Mus; Mutation; Nature; Normal tissue morphology; Northern Blotting; Pathway interactions; Pattern; Phenotype; Polyps; Predictive Value; Predisposition; Prevention; Proteins; Quantitative Trait Loci; RNA; Reporting; Research; Research Personnel; Resistance; Resources; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Sampling; Staging; Susceptibility Gene; System; Testing; Time; Transcript; Transgenic Organisms; Treatment outcome; Tumor Suppressor Genes; Variant; adenoma; congenic; design; genome database; in vivo; insight; mouse model; novel; offspring; phospholipase A2-II; positional cloning; prevent; protective effect; research study; response; segregation; text searching; tumor; tumor progression; tumorigenesis

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.

描述（由申请人提供）：影响癌症易感性的基因研究是一个快速发展的领域。该提案的重点是识别和表征影响胃肠道癌症发展的新型修饰基因座。我们选择的系统涉及肿瘤抑制基因，腺瘤性结肠息肉病（APC）。APC突变导致遗传性和散发性结直肠癌。ApcMin小鼠在APC基因的同源物中具有突变，并且在它们的小肠和大肠中形成多个腺瘤。QTL研究确定了一个基因座，Min修饰因子（Mom 1），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，分泌型II型磷脂酶A2（Pla 2g 2a）基因是负责至少一部分的Mom 1表型。虽然很明显存在其他修饰基因座，但由于Mom 1基因座在这些杂交中的分离，它们无法被鉴定。为了进一步剖析遗传修饰剂途径，我们通过交换C57 BL 6/J和C3 H/HeJ小鼠之间的Mom 1区域构建了相互的同源品系。这些品系导致通常易感的B6小鼠含有抗性Mom 1等位基因，类似地，抗性C3 H小鼠含有易感的Mom 1位点。QTL分析现已揭示了5个新修饰区的存在。我们建议分离和表征B6-C3 H相互同源菌株之间确定的最有效的修饰剂。我们将开发同类资源来研究新的Mom#位点的作用。此外，我们将细化每个Mom#基因座的遗传位置，使用位置和候选基因方法来识别负责Mom#表型的基因。最后，我们将进行几项生物测定，以进一步了解Mom#功能的分子机制。本文概述的研究将最终导致对这些修饰基因在肿瘤预防和治疗反应中的预测价值的认识，并为新型化学预防剂提供途径。我们认为，“一分预防胜过磅治疗”。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，我们希望能够开发新的方法来帮助预防癌症的发展。