Aberrant methylation of LINE-1, SLIT2, MAL and IGFBP7 in non-small cell lung cancer

Abstract

Genome-wide DNA hypomethylation and gene hypermethylation play important roles in instability and carcinogenesis. Methylation in long interspersed nucleotide element 1 (LINE-1) is a good indicator of the global DNA methylation level within a cell. Slit homolog 2 (SLIT2), myelin and lymphocyte protein gene (MAL) and insulin-like growth factor binding protein 7 (IGFBP7) are known to be hypermethylated in various malignancies. The aim of the present study was to assess the precise methylation levels of LINE-1, SLIT2, MAL and IGFBP7 in non-small cell lung cancer (NSCLC) using a pyrosequencing assay. Methylation of all regions was examined in 56 primary NSCLCs using a pyrosequencing assay. Changes in mRNA expression levels of SLIT2, MAL and IGFBP7 were measured before and after treatment with a demethylating agent. Methylation of these genes was also examined in 9 lung cancer cell lines using RT-PCR and a pyrosequencing assay. Frequencies of hypomethylation of LINE-1 and hypermethylation of SLIT2, MAL and IGFBP7, defined by predetermined cut off values, were 55, 64, 46 and 54% in NSCLCs, respectively and exhibited tumor-specific features. The hypermethylation of all genes was well correlated with changes in expression. The methylation level and frequency of MAL were significantly higher in smokers and in patients without EGFR mutations. Through accurate measurement of methylation levels using pyrosequencing, hypomethylation of LINE-1 and hypermethylation of SLIT2, MAL and IGFBP7 were frequently detected in NSCLCs and associated with various clinical features. Analysis of the methylation profiles of these genes may, therefore, provide novel opportunities for the therapy of NSCLCs.

Decreased MALL expression negatively impacts colorectal cancer patient survival

“…Increased LOH and methylation of the MALL gene was observed. This is consistent with previous reports in which MAL promoter hypermethylation was detected in cervical disease [21, 22] as well as several cancers, including non-small cell lung cancer [23], head and neck squamous cell carcinoma [19], cervical cancer [20, 24], ovarian cancer [25], gastric cancers [26], and colorectal cancer [27]. However, further detailed analyses of the mechanisms of MALL downregulation are necessary to examine whether LOH and methylation are cooperative events or different mechanisms as well as to determine if these events are found in the majority of colon and rectal cancers or only specific subsets.…”

Evaluation of IGFBP-7 DNA methylation changes and serum protein variation in Swedish subjects with and without type 2 diabetes

“…IGFBP-7 may play a tumor-suppressor role in carcinogenesis of these cancers, mainly through inactivation of its DNA methylation [22-25]. DNA methylation is involved in the regulation and expression of genes [26].…”

Long Interspersed Nucleotide Element 1 Hypomethylation Is Associated With Poor Prognosis of Lung Adenocarcinoma

“…In previous studies, LINE-1 hypomethylation was reported to be related to worse prognosis of NSCLC, and the methylation rate was significantly lower in squamous cell carcinoma than in AD [18,19]. Squamous cell carcinoma and AD are the 2 major histologic subtypes of NSCLC, and their pathogenesis and clinical behavior are different.…”