Analysis of hypermethylation and expression profiles of APC and ATM genes in patients with oral squamous cell carcinoma

Abstract

BackgroundAdenomatous polyposis coli (APC) and Ataxia-telangiectasia-mutated (ATM) gene products have an important role in cell cycle control and maintenance of genomic stability. Our aim was to analyze ATM and APC methylation and its relationship with oral squamous cell carcinoma (OSCC).Materials and methodsEighty-four OSCC tissues that have been fixed in paraffin along with 57 control oral samples have been used for analyzing promoter methylation of ATM and APC genes by Methylation Specific Polymerase Chain Reaction (MS-PCR). In addition, 10 cases of OSCC and the same of matched controls were examined for estimating expression of the above mentioned genes using Real-Time Reverse-Transcription PCR.ResultsObserved promoter methylations were 71.42% and 87.71% for the APC gene and 88.09% and 77.19% for the ATM gene in cases and controls, respectively. Analysis of these data showed that promoter methylation at APC was significantly different in cases compared to healthy controls (p = 0.01), but no difference was detected for the ATM gene. Furthermore, the mRNA expression levels did not differ statistically between cases and controls for both ATM (cases = 9, controls = 10) and APC (cases = 11, controls = 10) genes.ConclusionsOur results, for the first time, provide methylation profiles of ATM and APC genes in a sample of patients with OSCC in a southeast Iranian population. The present data support related evidence of APC methylation effect on OSCC development.

Aberrant gene-specific DNA methylation signature analysis in cervical cancer

“…57 ATM protein belongs to PI3/PI4-kinase family and is an important cell cycle-checkpoint kinase reported as hypermethylated in human colorectal cancer cell lines, oral SCCs, breast cancers, and brain tumors. [58][59][60][61] In addition to this, methylation of ATM promoter is correlated with radiosensitivity in colorectal cancers. 59 FGF18 is a fibroblast growth factor family member possessing cell survival and mitogenic activities and is involved in cell growth, morphogenesis, tumor growth, and invasion by regulation of actin cytoskeleton, PI3K, and fibroblast growth factor receptor (FGFR) signaling.…”

Quantitative methodology is critical for assessing DNA methylation and impacts on correlation with patient outcome

“…ABO was selected due to reports specifically in oral carcinomas that detected methylation of the gene, loss of expression of these epithelial antigens [ 28 ], and frequent alteration of chromosome 9q34 where the ABO gene resides [ 85 , 86 ]. Methylation of ATM was investigated due to a number of reasons: patients who suffer ataxia telangiectasia defined by ATM gene dysfunction are known to be predisposed to the development of oral carcinomas [ 87 ]; there are reports demonstrating high frequencies of ATM methylation in HNSCC [ 18 , 31 , 33 ]; ATM plays a crucial role in double-stranded DNA repair, and thus, gene dysfunction contributes to exquisite sensitivity to radiation treatment, which is a key therapeutic modality for the management of HNSCC [ 88 , 89 ]; and due to our previous investigation of the impact of other mechanisms of ATM gene loss in HNSCC [ 90 ]. BRCA1 was investigated due to its role in homologous DNA repair, and as part of the Fanconi Anemia/ BRCA pathway [ 35 , 91 , 92 ], with the known genetic predisposition of patients with Fanconi Anemia to develop malignancies including oral tongue and oral cavity squamous cell carcinomas [ 93 ].…”

ATM expression is attenuated by promoter hypermethylation in human ovarian endometriotic stromal cells

“…Accordingly, loss of functional ATM is associated with both decreased genomic integrity and increased cancer risk. Repression of ATM expression by DNA hypermethylation has been reported in head and neck carcinomas (Ai et al, 2004), oral squamous cell carcinoma (Rigi-Ladiz et al, 2011), colorectal cancers (Bai et al, 2004), non-small cell lung cancer (Safar et al, 2007), breast cancers (Vo et al, 2004), and malignant lymphomas (Huang et al, 2007). It has also been suggested that epigenetically repressed ATM might be responsible for resistance to DNA damage signals and the acquisition of the proliferative characteristics of endometriosis.…”