Molecular Genetics of Cancer Susceptibility

癌症易感性的分子遗传学

• 批准号: 7016379
• 负责人: Linda D Siracusa
• 金额: $ 33.72万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7016379
• 关键词: adenoma; cancer risk; cryopreservation; gene expression; gene mutation; genetic mapping; genetic susceptibility; genotype; immunocytochemistry; intestine neoplasm; laboratory mouse; light microscopy; loss of heterozygosity; molecular cloning; molecular genetics; molecular oncology; neoplasm /cancer genetics; polymerase chain reaction; quantitative trait loci

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.

描述（由申请人提供）：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 Min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形成多个腺瘤。QTL研究确定了一个基因座，Min的修饰因子（Mom 1），它映射到4号染色体的远端区域，极大地改变了ApcMin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Mom 1的强有力的候选人。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。表达和序列分析显示Mom 1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-/-区域的同源小鼠。在与ApcMin /+小鼠的杂交中使用这种新开发的同源品系，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，以确定可能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。