Expression level and methylation status of three tumor suppressor genes, DLEC1, ITGA9 and MLH1, in non-small cell lung cancer

Abstract

Despite therapeutic advances, lung cancer remains one of the most common causes of cancer-related death in the world. There is a need to develop biomarkers of diagnostic and/or prognostic value and to translate findings in basic science research to clinical application. Tumor suppressor genes (TSGs) represent potential useful markers for disease detection, progression and treatment target. We tried to elucidate the role of three 3p21.3 TSGs: DLEC1, ITGA9 and MLH1, in non-small cell lung cancer (NSCLC). We assessed their expression pattern by qPCR in 59 NSCLC tissues and in the matched macroscopically unchanged lung tissues. Additionally, we analyzed gene promoter methylation status by methylation-specific PCR in NSCLC samples. We did not find significant correlations between gene expression and methylation. In case of DLEC1 and ITGA9, expression levels were decreased in 71-78 % of tumor samples and significantly different between tumor and normal tissues (P = 0.0001). It could point to their diagnostic value. ITGA9 could also be regarded as a diagnostic marker differentiating NSCLC subtypes, as its expression level was significantly lower in squamous cell carcinoma (P = 0.001). The simultaneous down-regulation of DLEC1 and ITGA9 was observed in 52.5 % of NSCLCs. MSPs revealed high frequencies of gene promoter methylation in NSCLCs: 84 % for DLEC1 and MLH1 and 57 % for ITGA9. Methylation indexes reflected moderate gene methylation levels: 34 % for ITGA9, 27 % for MLH1 and 26 % for DLEC1. However, frequent simultaneous methylation of the studied genes in more than 50 % of NSCLCs suggests the possibility of consider them as a panel of epigenetic markers.

Genome‐wide copy number variation pattern analysis and a classification signature for non‐small cell lung cancer

“…In contrast to 3q gains in LUSC, a loss of most or all of 3p characterized both LUAD and LUSC, being more prominent in LUSC (Figure ). Losses of 3p were the first cytogenetic alteration found in lung cancers, occurring early during lung cancer pathogenesis, and multiple tumor suppressor genes are located in this region …”

Aberrant methylation of mutL homolog 1 is associated with increased risk of non‐small cell lung cancer

“…37 And frequent simultaneous methylation of DLEC1, ITGA9, and MLH1 in more than 50% NSCLC patients indicated the possibility of considering them as a panel of epigenetic markers in NSCLC. 31 However, Geng et al 39 found no significant differences in MLH1 methylation between AC and SCC in Chinese population. Coincidentally, in our case-control study in Chinese, MLH1 methylation difference was not statistical significance between AC and SCC.…”

“…Our ROC test indicated that MLH1 MSP method is a sensitive but not specific diagnostic method for NSCLC. Previous studies showed a panel of biomarkers for NSCLC . Recently, miRNA appeared to be valuable diagnostic candidate biomarkers which were employed for the diagnosis of NSCLC in early stages .…”

“…In addition, a panel of CDO1 , HOXA9, AJAP1 , PTGDR , UNCX , and MARCH11 methylation could be potential biomarkers for early detection of NSCLC with high sensitivity and specificity . And frequent simultaneous methylation of DLEC1 , ITGA9, and MLH1 in more than 50% NSCLC patients indicated the possibility of considering them as a panel of epigenetic markers in NSCLC . Future study might be performed to evaluate aberrant MLH1 methylation as a supplemental component in the diagnostic panel for NSCLC.…”

“…Previous studies showed a panel of biomarkers for NSCLC. [31][32][33][34] Recently, miRNA appeared to be valuable diagnostic candidate biomarkers which were employed for the diagnosis of NSCLC in early stages. 35 A diagnostic test based on miRNA-944 and miRNA-3662 showed 75.7% sensitivity and 82.3% specificity (AUC = 0.898) in distinguishing NSCLC from healthy individuals.…”