Molecular Genetics of Cancer Susceptibility

描述（由申请人提供）：研究影响癌症易感性的基因是一个快速发展的领域。小鼠遗传学的力量与扫描单个动物整个基因组的能力相结合，导致发现几个染色体区域含有赋予不同类型癌症易感性或抗性的基因。这项建议的重点是识别和表征影响胃肠道癌症发展的基因。我们的目标是使用新建立的基因小鼠系来确定影响癌症易感性的其他位点。我们选择的系统涉及肿瘤抑制基因大肠腺瘤性息肉病（APC）。APC突变导致遗传性和散发性结直肠癌。Apc Min小鼠在Apc基因的同系物中发生突变，并在其小肠和大肠中发生多发性腺瘤。QTL研究发现了一个位点，即Min修饰因子（Mom1），它位于4号染色体的远端区域，可以显著地修饰apcmin诱导的肿瘤数量。我们之前报道过分泌II型磷脂酶A2 （Pla2g2a）基因是Mom1的有力候选基因。小鼠近交系Pla2g2a等位基因类型与肿瘤易感性的一致性为100%。表达和序列分析显示Mom1易感菌株Pla2g2a活性为零。我们在CAST/Ei抗性自交系背景下建立了C57BL/6J Pla2g2a-/-区域的小鼠基因。利用这一新开发的同源菌株与ApcMin /+小鼠杂交，我们将分析后代的几个参数，测量肿瘤表型，并对后代的基因组进行QTL分析，以确定影响息肉多样性的其他位点。基因组的鉴定区域将进一步进行分子解剖，以确定其对癌症易感性的影响；这些研究将导致鉴定和表征负责改变易感性的基因。最终，对人类肿瘤中新发现的修饰基因位点的检查应该允许理解修饰基因对人类肿瘤发生、生长和进展的影响之间的关系。进一步的研究将最终导致对这些修饰基因在癌症诊断、预防和治疗中的价值的见解。

DESCRIPTION (provided by applicant): The study of genes that influence cancer susceptibility is a rapidly evolving field. The power of mouse genetics coupled with the ability to scan entire genomes of individual animals has led to the discovery that several chromosomal regions harbor genes conferring susceptibility or resistance to different types of cancers. This proposal is focused on identifying and characterizing genes that influence the development of cancers in the gastrointestinal tract. Our goals are to use newly established congenic mouse lines to identify additional loci influencing cancer susceptibility. The system we have chosen involves the tumor suppressor gene Adenomatous Polyposis Coli (APC). Mutations in APC cause inherited and sporadic colorectal cancers. Apc Min 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 (Mom1), which maps to the distal region of chromosome 4 that dramatically modifies ApcMin-induced tumor number. We previously reported that the secretory type II Phospholipase A2 (Pla2g2a) gene is a strong candidate for Mom1. Inbred strains of mice display 100% concordance between Pla2g2a allele type and tumor susceptibility. Expression and sequence analysis revealed that Mom1 susceptible strains are null for Pla2g2a activity. We have established mice congenic for the C57BL/6J Pla2g2a-/- region on the CAST/Ei resistant inbred strain background. Using this newly developed congenic strain in crosses with ApcMin /+ mice, we will analyze offspring for several parameters measuring tumor phenotype and perform QTL analyses on the genome of offspring to identify additional loci that can influence polyp multiplicity. The identified regions of the genome will be further subjected to molecular dissection to determine their influence on cancer susceptibility; these studies will lead to the identification and characterization of gene(s) responsible for altering susceptibility. Ultimately, examination of newly identified modifier loci in human tumors should allow an understanding of the relationship between the effects of modifier genes on human tumor initiation, growth and progression. Further investigations will ultimately lead to insights regarding the value of these modifier genes in cancer diagnostics, prevention and treatment.