Combined deletion and DNA methylation result in silencing of FAM107A gene in laryngeal tumors

Abstract

<p>Larynx squamous cell carcinoma (LSCC) is characterized by complex genotypes, with numerous abnormalities in various genes. Despite the progress in diagnosis and treatment of this disease, 5-year survival rates remain unsatisfactory. Therefore, the extended studies are conducted, with the aim to find genes, potentially implicated in this cancer. In this study, we focus on the <i>FAM107A</i> (3p14.3) gene, since we found its significantly reduced expression in LSCC by microarray profiling (Affymetrix U133 Plus 2.0 array). By RT-PCR we have confirmed complete <i>FAM107A</i> downregulation in laryngeal cancer cell lines (15/15) and primary tumors (21/21) and this finding was further supported by FAM107A protein immunohistochemistry (15/15). We further demonstrate that a combined two hit mechanism including loss of 3p and hypermethylation of <i>FAM107A</i> promoter region (in 9/15 cell lines (<i>p</i> < 0.0001) and in 15/21 primary tumors (<i>p</i> < 0.0001)) prevails in the gene transcriptional loss. As a proof of principle, we show that Decitabine - a hypomethylating agent – restores <i>FAM107A</i> expression (5 to 6 fold increase) in the UT-SCC-29 cell line, characterized by high DNA methylation. Therefore, we report the recurrent inactivation of <i>FAM107A</i> in LSCC, what may suggest that the gene is a promising tumor suppressor candidate involved in LSCC development.<br /></p>