Molecular Genetics of Cancer Susceptibility

对影响癌症易感性的基因的研究是一个快速发展的领域。小鼠遗传学的力量 扫描单个动物的整个基因组的能力导致了几个染色体区域的发现 港湾基因赋予不同类型癌症的易感性或抵抗力。这项提案的重点是确定 以及对影响胃肠道癌症发展的基因进行表征。我们的目标是利用 新建立的同源小鼠品系，以确定其他影响癌症易感性的基因座。我们所拥有的系统 SELECTED涉及肿瘤抑制基因腺瘤性息肉病结肠(APC)。APC基因突变导致遗传性和 散发性结直肠癌。APC Mi“小鼠在APC基因的同源物中存在突变，并发展为多发性 小肠腺瘤和大肠腺瘤。QTL研究确定了Min(Morn1)的一个修饰基因 映射到4号染色体的远端区域，该区域显著改变了APC_“诱导的肿瘤数量。我们之前 报道称分泌型磷脂酶A2(Pla2g2a)基因是Morn1的有力候选基因。近交系 小鼠的Pla2g2a等位基因类型与肿瘤易感性显示出100%的一致性。表达和序列 分析表明，MOM1敏感株对Pla2g2a活性为零。我们已经建立了小鼠的致病基因 C57BL/6J Pla2g2a-/-区位于Cast/Ei抗性自交系背景上。利用新开发的同源基因 在WTM.，-A-PC Mint/_L_小鼠中，我们将分析后代的几个参数来测量肿瘤表型和 对后代的基因组进行QTL分析，以确定可能影响息肉多样性的其他基因座。这个 已确定的基因组区域将进一步进行分子解剖，以确定它们对癌症的影响。 易感性；这些研究将导致对导致改变的基因(S)的鉴定和表征 敏感度。最终，对人类肿瘤中新发现的修饰基因座的检查应该允许 理解修饰基因对人类肿瘤启动、生长和生长的影响 进步。进一步的研究将最终导致对这些修饰基因在癌症中的价值的深入了解。 诊断、预防和治疗。

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 gcnes 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 Mi"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 (Morn1), which maps to the distal region of chromosome 4 that dramatically modifies Apc_"-induced tumor number. We previously reported that the secretory type II Phospholipase A2 (Pla2g2a) gene is a strong candidate for Morn1. Inbred strains of mice display 100% concordance between Pla2g2a allele type and tumor susceptibility. Expression and sequence analysis revealed that Moml susceptible strains are null for Pla2g2a activity. We have established mice eongenic for the C57BL/6J Pla2g2a-/- region on the CAST/Ei resistant inbred strain background. Using this newly developed congenic strain in crosses wt.m., -A-pC Mint/_l_ 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.