Molecular Genetics of Cancer Susceptibility

影响癌症易感性的基因研究是一个快速发展的领域。老鼠遗传学的力量 能够扫描单个动物的整个基因组， 含有对不同类型癌症易感性或抗性的基因。该建议的重点是确定 并表征影响胃肠道癌症发展的GCNE。我们的目标是利用 新建立的同类小鼠系，以确定影响癌症易感性的其他基因座。我们的系统 选择的肿瘤抑制基因涉及腺瘤性结肠息肉病（APC）。APC突变导致遗传性和 散发性结直肠癌Apc Mi“小鼠在APC基因的同源物中具有突变，并且发展多个突变。 在他们的小肠和大肠里都有腺瘤。QTL研究确定了一个位点，Min修饰子（Morn 1）， 映射到4号染色体的远端区域，显著改变Apc_"诱导的肿瘤数量。我们之前 报道了分泌型II型磷脂酶A2（Pla 2g 2a）基因是Morn 1的强候选基因。近交系 小鼠的Pla 2g 2a等位基因类型与肿瘤易感性之间显示出100%的一致性。表达和序列 分析显示Mom 1敏感菌株不具有Pla 2g 2a活性。我们已经建立了小鼠的基因， C57 BL/6 J Pla 2g 2a-/-区在CAST/Ei抗性近交系背景上的表达。利用这种新开发的同类基因 十字形应变wt.m.，-A-pC Mint/_l_小鼠，我们将分析后代的几个测量肿瘤表型的参数， 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。的 基因组中已确定的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;这些研究将导致识别和表征基因负责改变 易感性最后，对人类肿瘤中新鉴定的修饰基因座的检查应该允许对肿瘤进行基因组学研究。 了解修饰基因对人类肿瘤发生、生长和转移的影响之间的关系， 进展进一步的研究将最终导致关于这些修饰基因在癌症中的价值的见解 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.