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

• Applicant: Dr. Johannes F Gebert
• Subject Area: Pathology
• Term: from 2006 to 2009
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 24817972

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.

• DFG Programme: Research Grants