Promoter hypermethylation of DNA repair genes MLH1 and MSH2 in adenocarcinomas and squamous cell carcinomas of the lung

Abstract

Five years survival of lung cancer is 16%, significantly lower than in prostate (99.9%), breast (88.5%) and colon (64.1%) carcinomas. When diagnosed in the surgical stage it increases to 50% but this group only comprises 14-16% of the cases. DNA methylation has emerged as a potential cancer-specific biomarker. Hypermethylation of CpG islands located in the promoter regions of tumour suppressor genes is now firmly established as an important mechanism for gene inactivation. This retrospective study included 40 squamous cell carcinomas and 40 adenocarcinomas in various surgical TNM stages to define methylation profile and possible silencing of DNA repair genes - MLH1 and MSH2 - using Methylation-Specific PCR and protein expression by immunohistochemistry in tumoural tissue, preneoplastic lesions and respiratory epithelium with normal histological features. The protein expression of MLH1 and MSH2 genes, in the available preneoplastic lesions and in normal cylindrical respiratory epithelium appeared reduced. The frequency of promoter hypermethylation found on these DNA repair genes was elevated, with a higher prevalence of methylation of MLH1 gene in 72% of squamous cell carcinoma. The differences are not so obvious for MSH2 promoter hypermethylation. No correlation was found among the status of methylation, the protein expression and the clinicopathological characteristics. With a larger study, a better characterization of the hypermethylation status of neoplastic and preneoplastic lesions in small biopsies would be achieved, inherent to tumour histology, heterogeneity and preservation, and finally differences in the study population to elucidate other possible mechanisms of altered expression of the hMLH1 and hMSH.

Low-Dose Decitabine-Based Chemoimmunotherapy for Patients with Refractory Advanced Solid Tumors: A Phase I/II Report

“…DNA methylation typically occurs at the 5′-position of the cytosine ring within cytosine-phosphate-guanine (CpG) dinucleotides, and DNA methyltransferases (DNMTs) catalyze this reaction [3, 4]. In normal cells, CpG islands of tumor suppressors are usually unmethylated; however, hypermethylation of CpG promoters occurs frequently in tumors [5, 6]. DNA demethylation has the potential to reverse promoter hypermethylation in tumor cells and lead to the reexpression of aberrantly silenced genes, such as tumor suppressor genes (TSGs) of p16 and p15 [7] and cancer testis antigens (CTA) of MAGEA-1 and MAGEA-3 [8], and to induce the sensitivity of tumor cell to anticancer agents.…”

DNA methylation profile and expression of surfactant protein A2 gene in lung cancer

“…Aberrant DNA methylation of gene promoters has previously been observed in various lung cancers (10, 13–15, 47, 48). Maintenance of methylation patterns is controlled by DNA methyltransferases (DNMT1, DNMT3), in response to various insults and environmental exposures (1, 6, 49).…”

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

“…Walter et al have demonstrated that members of the DNA‐repair pathway, such as MLH1 , were correlated significantly with lung tumors classification in German. Gomes et al found MLH1 methylation pattern seemed to vary substantially by histological type, with a higher methylation in SCC in Portuguese. However, Geng et al found no significant differences in MLH1 methylation between AC and SCC in Chinese population.…”

“…Recently, several studies reported aberrant MLH1 promoter hypermethylation in NSCLC patients . However, using MLH1 methylation in the diagnosis for NSCLC was still debatable.…”

“…12 Recently, several studies reported aberrant MLH1 promoter hypermethylation in NSCLC patients. [16][17][18][19] However, using MLH1 methylation in the diagnosis for NSCLC was still debatable. In the present study, we obtained 111 NSCLC to determine whether MLH1 promoter methylation played a role in NSCLC in Han Chinese.…”