Effects of long-term aspirin use on molecular alterations in precancerous gastric mucosa in patients with and without gastric cancer

Abstract

The risk of gastric cancer (GC) remains even after H. pylori eradication; thus, other combination treatments, such as chemopreventive drugs, are needed. We evaluated the effects of aspirin on genetic/epigenetic alterations in precancerous conditions, i.e., atrophic mucosa (AM) and intestinal metaplasia (IM), in patients with chronic gastritis who had taken aspirin for more than 3 years. A total of 221 biopsy specimens from 74 patients, including atrophic gastritis (AG) cases without aspirin use (control), AG cases with aspirin use (AG group), and GC cases with aspirin use (GC group), were analyzed. Aspirin use was associated with a significant reduction of CDH1 methylation in AM (OR: 0.15, 95% CI: 0.06-0.41, p = 0.0002), but was less effective in reversing the methylation that occurred in IM. Frequent hypermethylation including that of CDH1 in AM increased in the GC group compared to the AG group, and CDH1 methylation was an independent predictive marker of GC (OR: 8.50, 95% CI: 2.64-25.33, p = 0.0003). In patients with long-term aspirin use, the changes of molecular events in AM but not IM may be an important factor in the reduction of cancer incidence. In addition, methylation of the CDH1 gene in AM may be a surrogate of GC.Helicobacter pylori (H. pylori) infection causes non-atrophic gastritis, which progresses to atrophic gastritis, intestinal metaplasia (IM), dysplasia, and finally, gastric cancer (GC) 1 . Thus, the International Agency for Research on Cancer has concluded that H. pylori is a class I human carcinogen 2 . To date, some meta-analyses have shown that H. pylori eradication reduced the risk of GC in patients with chronic gastritis who underwent endoscopic resection (ER) for early GC 3-7 . However, a recent study from Japan showed that even after H. pylori infection was cured and gastric inflammation was eliminated, there was still a risk of GC in the long-term 8 . Additionally, metachronous GC occurred to some degree in patients who had H. pylori infection eradicated following ER for early GC 9-13 . Thus, it remains controversial if H. pylori eradication suppresses the development of GC. To reduce the risk of GC after H. pylori eradication, other combination treatments such as anti-inflammatory agents and dietary or nutritional intervention are needed.Some studies including meta-analyses have reported that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a reduced risk of both colorectal cancer and GC [14][15][16][17] . Their anti-carcinogenetic effects have been attributed to inhibition of the cyclooxygenase pathway and their anti-inflammatory abilities 18,19 . The roles of a number of genetic and epigenetic alterations, including microsatellite instability (MSI) and promoter hypermethylation of multiple tumor-related genes, are reportedly involved in GC and precancerous conditions of the stomach [20][21][22][23][24][25][26][27][28][29][30][31][32][33] . The CpG island methylator phenotype (CIMP), characterized by extensive

Preventing Metachronous Gastric Cancer after the Endoscopic Resection of Gastric Epithelial Neoplasia: Roles of <i>Helicobacter pylori</i> Eradication and Aspirin

“…This procedure (i.e., LCM), might provide more information from atrophic or IM glands than would the use of whole tissue material with regard to gastric carcinogenesis in the precancerous conditions. 32,37,38,92 Although it has been reported that miR-124a-3 and miR-34b/c methylations in the background mucosa were associated with an increased risk of developing MGCs, 33,34,48,49 in our previous study the methylations of miR-124a-3 and miR-34c were mostly observed in IM, and only rarely in atrophy. 38 Thus, these results indicate that the methylation of these miRNA genes might be a specific marker expressed in IM and might not necessarily be a risk marker for GC.…”

“…Our previous study also showed that long-term aspirin use (≥3 years) was associated with a significant reduction of CDH1 methylation in atrophy (OR, 0.15; 95% CI, 0.06 to 0.41; p=0.0002), but was less effective in reversing the methylation that occurred in IM. 37 MSI did not change significantly after taking aspirin in either patient with atrophy or those with IM. 37 Interestingly, CIMP in IM, which is a surrogate marker of GC, 38 decreased in patients with chronic gastritis who regularly took aspirin for more than three years.…”

“…67 Indeed, we reported that the incidence of molecular events related to carcinogenesis was significantly higher in IM than in atrophy (non-IM), irrespective of the presence or absence of H. pylori infection and GC in the background mucosa, 37,38 and H. pylori eradication and long-term aspirin use were less effective in reversing the methylation that occurred in IM than in atrophy even in a long-term follow-up (median follow-up period: 5 years in H. pylori-eradication cases and 6.3 years in NSAIDs/aspirin users). 37,38 Additionally, H. pylori eradication was associated with a significant reduction of CIMP, CDH1, and miR-124a-3 methylation only in atrophy but not in IM. 38 To date, we have analyzed molecular events in atrophy and IM separately, as precancerous conditions, using laser cap- ture microdissection (LCM).…”

“…37 Interestingly, CIMP in IM, which is a surrogate marker of GC, 38 decreased in patients with chronic gastritis who regularly took aspirin for more than three years. 37 Therefore, long-term aspirin use, as an additional chemopreventive therapy, may help prevent GC development in patients with IM ( Fig. 1).…”

“…There have been only a few studies on molecular alterations in the gastric mucosa in patients taking regular aspirin; 37,91 to our knowledge, there have been no studies on the changes of somatic mutations and CIN by aspirin administration. Tahara et al 91 showed that chronic aspirin use was associated with a lower risk of CDH1 methylation, especially in H. pylori-positive subjects (nonuser [49.5%] vs user [19.0%]: OR, 0.24; 95% CI, 0.08 to 0.76; p=0.01).…”