Identification of AIM1 as a hypermethylation-inactivated tumor suppressor gene in HNSCC

Abstract

Problem: Hypermethylation of tumor suppressor gene (TSG) promoter regions has been described for a limited number of genes in head and neck squamous cell carcinoma (HNSCC). We used a genome-wide strategy to identify AIM1 as a putative tumor suppressor gene in HNSC that is inactivated by promoter methylation. Methods: HNSCC cell lines were treated with a demethylating agent to disinhibit expression of putative TSGs. Identification of candidates was based on significant expression increases compared to untreated controls on cDNA microarrays. Genes downregulated in primary HNSCC were identified by comparison of normal tissue and tumors using similar arrays. Downregulated genes common to these groups were verified by RT-PCR and subjected to PCR-based methylation analysis in primary tumors. Results: AIM1 (absent in melanoma 1), a putative TSG on chromosome 6q originally described in melanoma, exhibits promoter hypermethylation in 28% in a study of 47 primary HNSCC. AIM1 hypermethylation was only 8% in paired controls, suggesting a specific contributory role in head and neck cancer tumorigenesis ( P = 0.011). Conclusion: Genome-wide screening for promoter hypermethylation-inactivated genes in primary HNSCC and cell lines identified AIM1 as a putative tumor suppressor gene potentially important in HNSCC development. Significance: This study identifies a putative tumor suppressor gene in HNSCC. Further studies may discover a role for AIM1 in the tumorigenesis of many cancer types. Support: Supported in part by a NIH T32.