Role of AIM2, a selected target gene of microsatellite instability, in the pathogenesis of DNA mismatch repair-deficient colon cancers

AIM2（微卫星不稳定性选定靶基因）在 DNA 错配修复缺陷型结肠癌发病机制中的作用

• 批准号: 24817972
• 负责人: Dr. Johannes F Gebert
• 金额: --
• 依托单位: Abteilung für Angewandte Tumorbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2008-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/24817972?language=en
• 关键词: Role; AIM2; selected; target; gene

Genetic instability and accumulation of mutations is a major characteristic of malignant tumors. In colon cancer, the type and spectrum of affected genes markedly differs between chromosomal unstable (CIN) and microsatellite unstable (MSI) tumors. In CIN tumors the most frequently mutated growth regulating genes have been well characterized as members of signaling pathways, whereas the pathways of carcinogenesis in MSI tumors are largely unknown. In consequence of a defective mismatch repair system, MSI tumors accumulate frameshift mutations in multiple genes harboring repetitive DNA sequences, only a subset of which is expected to promote cancer progression. By using a statistical model that we recently proposed to predict mutations with functional impact on MSI tumors, we identified 26 candidate tumor suppressor genes, 20 of which were previously not reported to be involved in colon carcinogenesis. One candidate gene - AIM2 (absent in melanoma 2) - belongs to the HIN-200 family of interferon-inducible genes which mediate growth inhibition in a variety of different cell types. The biologic function of AIM2 in colon cells however, is unknown so far. Our frameshift mutation analyses of the cMS sequence in AIM2 revealed mutations in more than 50% of MSI colorectal adenomas and carcinomas. Notably, we detected a high frequency of AIM2 biallelic mutations (>40%) indicating complete loss of function in MSI colon cell lines and primary MSI colon carcinomas and adenomas, albeit at lower frequency. Preliminary data suggest that AIM2 causes cell death when transiently expressed in AIM2 deficient MSI colon cancer cell lines. We here propose to characterize AIM2 function and to analyse its impact on the pathogenesis of MSI cancers. Detailed understanding of AIM2 function might help to improve diagnostic and therapy of this aggressively growing cancer.

遗传不稳定性和突变的积累是恶性肿瘤的主要特征。在结肠癌中，受影响基因的类型和谱在染色体不稳定（CIN）和微卫星不稳定（MSI）肿瘤之间显着不同。在CIN肿瘤中，最常突变的生长调节基因已被很好地表征为信号传导途径的成员，而MSI肿瘤中的致癌途径在很大程度上是未知的。由于错配修复系统的缺陷，MSI肿瘤在携带重复DNA序列的多个基因中积累移码突变，预计只有其中的一个子集会促进癌症进展。通过使用我们最近提出的预测突变对MSI肿瘤的功能影响的统计模型，我们确定了26个候选肿瘤抑制基因，其中20个以前没有报道参与结肠癌发生。一个候选基因-AIM 2（在黑素瘤2中缺失）-属于干扰素诱导基因的HIN-200家族，其在多种不同细胞类型中介导生长抑制。然而，AIM 2在结肠细胞中的生物学功能迄今尚不清楚。我们对AIM 2中cMS序列的移码突变分析揭示了超过50%的MSI结直肠腺瘤和癌中的突变。值得注意的是，我们检测到高频率的AIM 2双等位基因突变（>40%），表明MSI结肠细胞系和原发性MSI结肠癌和腺瘤中的功能完全丧失，尽管频率较低。初步数据表明，当在AIM 2缺陷型MSI结肠癌细胞系中瞬时表达时，AIM 2导致细胞死亡。在这里，我们建议表征AIM 2功能，并分析其对MSI癌症发病机制的影响。对AIM 2功能的详细了解可能有助于改善这种积极生长的癌症的诊断和治疗。