LINE-1 hypomethylation is not a common event in preneoplastic stages of gastric carcinogenesis

Juozas Kupcinskas,Giedre Smailyte,Jurgita Skieceviciene,Limas Kupcinskas,Ruta Steponaitiene,Alexander Link,Peter Malfertheiner,Cosima Langner

doi:10.1038/s41598-017-05143-0

Abstract

LINE-1 hypomethylation is widely accepted as marker for global genomic DNA hypomethylation, which is a frequent event in cancer. The aim of the study was to evaluate LINE-1 methylation status at different stages of gastric carcinogenesis and evaluate its prognostic potential in clinical settings. LINE-1 methylation was analyzed in 267 tissue samples by bisulfite pyrosequencing including primary colorectal cancer tissues (T-CRC) with corresponding adjacent colon mucosa (N-CRC), gastric cancer tissues (T-GC) with corresponding gastric mucosa (N-GC), normal gastric tissues (N), chronic non-atrophic and atrophic gastritis (CG). LINE-1 methylation level was lower in both T-GC and T-CRC when compared to paired adjacent tissues. No difference was observed for LINE-1 methylation status between patients with normal gastric mucosa, CG and N-GC. LINE-1 methylation in T-GC but not N-GC tended to correlate with age. Subgroup stratification analysis did not reveal significant differences in LINE-1 methylation status according to tumor stage, anatomical location, histological subtype, differentiation grade. We observed similar overall survival data between patients with high or low LINE-1 levels. In summary, LINE-1 hypomethylation is a characteristic feature in GC but not very common in early preneoplastic stages of gastric carcinogenesis. Prognostic role of LINE-1 hypomethylation in GC patients could not be confirmed in this cohort.

Highlights

Gastric cancer (GC) remains a major healthcare burden across the globe and ranks as the second most common cause of cancer-related mortality[1]
Methylation status in Long Interspersed Nucleotide Element 1 (LINE-1) has been extensively studied in colorectal cancer (CRC); we included a group of patients with CRC for comparative analysis (Table 1)
Findings of our study provide a detailed characterization of LINE-1 methylation status across preneoplastic and neoplastic stages of gastric carcinogenesis

Summary

Introduction

Gastric cancer (GC) remains a major healthcare burden across the globe and ranks as the second most common cause of cancer-related mortality[1]. Hypomethylation of the entire genome partially results from demethylation in repetitive elements that account for about a half of the human genome This is essential in gene regulation and genomic stability[8]. LINE-1 methylation levels in tissues and blood samples of gastric cancer patients have been analyzed in several studies previously suggesting lower LINE-1 methylation as a characteristic event in GC12, 14–17. The analysis of LINE-1 methylation levels in DNA samples derived from blood of GC patients suggests potential diagnostic implications[16, 17]. The data on LINE-1 methylation status across different stages of gastric carcinogenesis are still limited. Most of reported studies have been conducted on Asian GC patients, while data on LINE-1 methylation levels in European subjects with GC and premalignant gastric lesions is largely unexplored[14]. For the evaluation of the prognostic role of LINE-1 methylation, we performed survival analyses

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