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The putative tumor suppressor AIM2 is frequently affected by different genetic alterations in microsatellite unstable colon cancers.
Genes Chromosomes Cancer. 2007 Dec; 46(12):1080-9.GC

Abstract

Mismatch repair (MMR) deficiency is a major mechanism of colorectal tumorigenesis that is observed in 10-15% of sporadic colorectal cancers and those associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. MMR deficiency leads to the accumulation of mutations mainly at short repetitive sequences termed microsatellites, constituting the high level microsatellite instability (MSI-H) phenotype. In recent years, several genes have been described that harbor microsatellites in their coding region (coding microsatellites, cMS) and are frequently affected by mutations in MMR-deficient cancers. However, evidence for a functional role of most of the known cMS-containing genes is missing, and further analyses are needed for a better understanding of MSI tumorigenesis. Here, we examined in detail alterations of the absent in melanoma 2 (AIM2) gene that shows a high frequency of cMS frameshift mutations in MSI-H colorectal, gastric, and endometrial tumors. AIM2 belongs to the HIN-200 family of interferon (IFN)-inducible proteins, its role in colon carcinogenesis, however, is unknown. Sequencing of the entire coding region of AIM2 revealed a high frequency of frameshift and missense mutations in primary MSI-H colon cancers (9/20) and cell lines (9/15). Biallelic AIM2 alterations were detected in 8 MSI-H colon tumors and cell lines. In addition, AIM2 promoter hypermethylation conferred insensitivity to IFN-gamma-induced AIM2 expression of three MSI-H colon cancer cell lines. These results demonstrate that inactivation of AIM2 by genetic and epigenetic mechanisms is frequent in MMR-deficient colorectal cancers, thus suggesting that AIM2 is a mutational target relevant for the progression of MSI-H colorectal cancers.

Authors+Show Affiliations

Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 220/221, D-69120 Heidelberg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17726700

Citation

Woerner, Stefan M., et al. "The Putative Tumor Suppressor AIM2 Is Frequently Affected By Different Genetic Alterations in Microsatellite Unstable Colon Cancers." Genes, Chromosomes & Cancer, vol. 46, no. 12, 2007, pp. 1080-9.
Woerner SM, Kloor M, Schwitalle Y, et al. The putative tumor suppressor AIM2 is frequently affected by different genetic alterations in microsatellite unstable colon cancers. Genes Chromosomes Cancer. 2007;46(12):1080-9.
Woerner, S. M., Kloor, M., Schwitalle, Y., Youmans, H., Doeberitz, M. v., Gebert, J., & Dihlmann, S. (2007). The putative tumor suppressor AIM2 is frequently affected by different genetic alterations in microsatellite unstable colon cancers. Genes, Chromosomes & Cancer, 46(12), 1080-9.
Woerner SM, et al. The Putative Tumor Suppressor AIM2 Is Frequently Affected By Different Genetic Alterations in Microsatellite Unstable Colon Cancers. Genes Chromosomes Cancer. 2007;46(12):1080-9. PubMed PMID: 17726700.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The putative tumor suppressor AIM2 is frequently affected by different genetic alterations in microsatellite unstable colon cancers. AU - Woerner,Stefan M, AU - Kloor,Matthias, AU - Schwitalle,Yvette, AU - Youmans,Hanni, AU - Doeberitz,Magnus von Knebel, AU - Gebert,Johannes, AU - Dihlmann,Susanne, PY - 2007/8/30/pubmed PY - 2007/12/27/medline PY - 2007/8/30/entrez SP - 1080 EP - 9 JF - Genes, chromosomes & cancer JO - Genes Chromosomes Cancer VL - 46 IS - 12 N2 - Mismatch repair (MMR) deficiency is a major mechanism of colorectal tumorigenesis that is observed in 10-15% of sporadic colorectal cancers and those associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. MMR deficiency leads to the accumulation of mutations mainly at short repetitive sequences termed microsatellites, constituting the high level microsatellite instability (MSI-H) phenotype. In recent years, several genes have been described that harbor microsatellites in their coding region (coding microsatellites, cMS) and are frequently affected by mutations in MMR-deficient cancers. However, evidence for a functional role of most of the known cMS-containing genes is missing, and further analyses are needed for a better understanding of MSI tumorigenesis. Here, we examined in detail alterations of the absent in melanoma 2 (AIM2) gene that shows a high frequency of cMS frameshift mutations in MSI-H colorectal, gastric, and endometrial tumors. AIM2 belongs to the HIN-200 family of interferon (IFN)-inducible proteins, its role in colon carcinogenesis, however, is unknown. Sequencing of the entire coding region of AIM2 revealed a high frequency of frameshift and missense mutations in primary MSI-H colon cancers (9/20) and cell lines (9/15). Biallelic AIM2 alterations were detected in 8 MSI-H colon tumors and cell lines. In addition, AIM2 promoter hypermethylation conferred insensitivity to IFN-gamma-induced AIM2 expression of three MSI-H colon cancer cell lines. These results demonstrate that inactivation of AIM2 by genetic and epigenetic mechanisms is frequent in MMR-deficient colorectal cancers, thus suggesting that AIM2 is a mutational target relevant for the progression of MSI-H colorectal cancers. SN - 1045-2257 UR - https://www.unboundmedicine.com/medline/citation/17726700/The_putative_tumor_suppressor_AIM2_is_frequently_affected_by_different_genetic_alterations_in_microsatellite_unstable_colon_cancers_ L2 - https://doi.org/10.1002/gcc.20493 DB - PRIME DP - Unbound Medicine ER -