Loci Affecting Colon Cancer Susceptibility

影响结肠癌易感性的位点

• 批准号: 6953436
• 负责人: ROSEMARY W ELLIOTT
• 金额: $ 31.45万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953436
• 关键词: chemical carcinogenesis; colon neoplasms; disease /disorder model; gene environment interaction; genetic mapping; genetic models; genetic regulatory element; genetic susceptibility; inbreeding; laboratory mouse; microarray technology; model design /development; neoplasm /cancer genetics

DESCRIPTION (provided by applicant): Colon cancer is one of the most frequent human malignancies, with 150,000 new cases and 60,000 deaths per year in the United States. Some of the molecular changes involved in the development of colon tumors are known, and in about 20% of the cases the genetic basis for colon tumor susceptibility has been identified, either as a mutation in the Apc locus or as a mutation in a locus encoding a protein involved in DNA synthesis/repair. The genetic basis for susceptibility to sporadic rumors, about 80% of cases, is unknown and is probably complex. We have been working with a mouse model for susceptibility to carcinogen-induced colon cancer, first using the carcinogen 1,2-dimethylhydrazine dihydrochloride (DMH) and later its metabolite azoxymethane, (AOM), which is more stable and requires fewer injections. Strain ICR/Ha is highly sensitive to DMH-induced colon tumors, while strain C57BL/6Ha is resistant. The (ICRxC57BL/6) F1 hybrid was backcrossed to C57BL/6Ha, and 122 progeny were treated with DMH. Colon tumors were detected in some of these progeny, which were typed for genetic loci on all chromosomes. QTL analysis using the number of tumors per animal suggested that four chromosomal regions, on Chrs 5, 12, 13 and 14, contained genes with allelic differences that affected the number of carcinogen-induced colon tumors. A set of congenic strains have been constructed that separately place the sensitive alleles at each of the four chromosomal regions on the background of the resistant strain. Animals from generation N5F2 of each of these strains were treated with DMH and colon tumors were found in most animals from all four congenic lines. Subcongenic lines have been generated for all chromosomes and two sets (Chrs 12 and 14) have been tested and are sensitive to AOM. We now propose four Specific Aims. In the first aim we plan to further refine the mapping of each gene by decreasing the length of the congenic region. In the second aim we plan to refine our protocol for use of AOM to determine the best injection schedule so that all ICR/Ha mice develop tumors. Following this, animals from the subcongenic strains will be tested to identify the smallest subcongenic interval containing the gene determining sensitivity. In the third aim we will address the question of what genetic changes occur in the tumors themselves, and whether there is specificity such that tumors arising from any one of the congenic strains show a consistent profile of changes.

描述（由申请人提供）：结肠癌是最常见的人类恶性肿瘤之一，在美国每年有150，000例新发病例和60，000例死亡。一些参与结肠肿瘤发展的分子变化是已知的，并且在约20%的病例中，结肠肿瘤易感性的遗传基础已经被鉴定为Apc基因座中的突变或编码参与DNA合成/修复的蛋白质的基因座中的突变。大约80%的病例对散发性谣言易感的遗传基础是未知的，可能是复杂的。我们一直在研究致癌物诱导的结肠癌易感性的小鼠模型，首先使用致癌物1，2-二甲基肼二盐酸盐（DMH），后来使用其代谢物氧化偶氮甲烷（AOM），后者更稳定，需要较少的注射。ICR/Ha菌株对DMH诱导的结肠肿瘤高度敏感，而C57 BL/6 Ha菌株具有抗性。将（ICRxC 57 BL/6）F_1与C57 BL/6 Ha回交，用DMH处理122个后代。在这些后代中的一些后代中检测到结肠肿瘤，这些后代在所有染色体上的遗传位点上进行了分型。使用每只动物肿瘤数量的QTL分析表明，在第5、12、13和14条染色体上的四个染色体区域含有影响致癌物诱导的结肠肿瘤数量的等位基因差异的基因。已经构建了一组同源菌株，其分别将敏感等位基因置于抗性菌株背景上的四个染色体区域中的每一个。用DMH处理来自这些品系中的每一个的N5 F2代的动物，并且在来自所有四个同源系的大多数动物中发现结肠肿瘤。所有染色体都产生了亚同源系，并测试了两组（Chrs 12和14），它们对AOM敏感。我们现在提出四个具体目标。在第一个目标中，我们计划通过减少同源区域的长度来进一步完善每个基因的定位。在第二个目标中，我们计划完善AOM的使用方案，以确定最佳注射时间表，以便所有ICR/Ha小鼠都产生肿瘤。此后，将对亚同源菌株的动物进行检测，以确定包含决定灵敏度的基因的最小亚同源间隔。在第三个目标中，我们将解决肿瘤本身发生了什么遗传变化的问题，以及是否存在特异性，使得来自任何一种同源株的肿瘤显示出一致的变化特征。