GENETIC MODIFIERS OF COLORECTAL TUMORIGENESIS

影响职业易感性的基因研究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。我们的目标有两个：1)进一步研究数量性状位点（QTL）的第一个候选基因，2)使用新建立的突变和同源小鼠系来鉴定含有影响职业易感性基因的其他染色体区域。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基因组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研究确定了一个位点，即Min修饰子（Mom1），它位于4号染色体的远端区域。MOM1位点显著改变Apc/ min诱导的肿瘤数量。我们之前报道过分泌型磷脂酶A2 （PLA2g2a）基因是Mm1位点的一个强有力的候选者。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。我们建议进一步研究Pla2g2a基因及其在小鼠和人类肿瘤中的作用。此外，我们还发现了一种自发突变（Mom2），它似乎是Apc/Min小鼠肿瘤发生的有效抑制因子。我们建议完善Mom2位点的定位，并研究候选基因。最后，我们在一个具有抗性的近交系背景上建立了Pla2q2a-/-的小鼠基因。在指定的杂交中使用这个新的同源菌株，我们将分析后代的肿瘤数量和QTL分析，以确定基因组中可能影响息肉形成的其他区域。对人类肿瘤中PLA2G2A和新发现的修饰基因位点的进一步研究将有助于理解修饰基因对肿瘤形成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肿瘤预防和治疗反应中的预测价值的见解。

The study of genes that influence career 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 two-fold: 1) to further investigated the first candidate gene identified for a quantitative trait locus (QTL), and 2) to use newly established mutant and congenic mouse lines to identify additional chromosomal regions that harbor genes influencing career 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 genome 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. The MOM1 locus dramatically modifies Apc/Min-induced tumor number. We previously reported that the secretory type II Phospholipase A2 (PLA2g2a) gene is a strong candidate for the Mm1 locus. 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 propose to examine further the Pla2g2a gene and its effects in both mouse and human tumors. In addition, we have discovered a spontaneous mutation (Mom2) that appears to be a potent suppressor of tumorigenesis in Apc/Min mice. We propose to refine the map location pf the Mom2 locus and investigate candidate genes. Finally, we have established mice congenic for Pla2q2a-/- on an otherwise resistant inbred strain background. Using this new congenic strain in designated crosses, we will analyze offspring for tumor number and QTL analyses to identify additional regions of the genome that can influence polyp formation. The further examination of both PLA2G2A and newly identified modifier loci in human tumors should allow an understanding of the relationship between the effects of modifier genes on tumor formation and progression. Further investigations will ultimately lead to insights regarding the predictive value of these modifier genes in tumor prevention and response to treatment.