Molecular Genetics of Cancer Susceptibility

超出所提供的空间。影响癌症易感性的基因研究是一个快速发展的领域。小鼠遗传学的力量加上扫描单个动物整个基因组的能力，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。该提案的重点是确定和表征影响胃肠道癌症发展的gcnes。我们的目标是使用新建立的同类系小鼠，以确定其他基因座影响癌症的易感性。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。Apc Mi“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发展出多个腺瘤。QTL研究确定了一个基因座，Min修饰因子（Morn 1），它定位于4号染色体的远端区域，显著修饰Apc_"诱导的肿瘤数量。我们以前报道，分泌型II型磷脂酶A2（Pla 2g 2a）基因是一个强有力的候选人Morn 1。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100%一致性。表达和序列分析揭示Moml敏感菌株不具有Pla 2g 2a活性。我们已经在CAST/Ei抗性近交系背景上建立了C57 BL/6 J Pla 2g 2a-/-区域的基因型小鼠。在杂交中使用这种新开发的同类菌株，-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，并对后代的基因组进行QTL分析，以鉴定可影响息肉多样性的其他基因座。基因组的识别区域将进一步进行分子解剖，以确定它们对癌症易感性的影响;这些研究将导致负责改变易感性的基因的识别和表征。最后，在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。性能现场=

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================