This case–control study nested within the ATBC Study cohort provides evidence, for the first time to our knowledge, of a statistically significant increase in the risk of both GNCA and EGJA for individuals with lower baseline serum ghrelin concentrations. This statistically significant increased risk of gastric cancer was independent of the baseline pepsinogen I concentration and H pylori infection and was present even for patients diagnosed more than 10 years after baseline. In contrast, the increased risk of GNCA and EGJA noted for those with low serum pepsinogen I was confined to cancers developing less than 5 years after baseline.
Although to the best of our knowledge, no previous studies have reported the relationship between serum ghrelin concentration and the risk of gastric cancer, one study nested in a multiphasic health checkup cohort in the Kaiser Permanente Medical Care Program (California) analyzed serum ghrelin concentrations in 31 esophageal adenocarcinoma patients and 79 matched control subjects (15
). Similar to our results in EGJA cancers, the authors found an adverse relationship between lower serum ghrelin and esophageal adenocarcinoma for those in the lowest quartile of serum ghrelin concentration (OR = 5.55, 95% CI = 1.28 to 25.0). This association with esophageal adenocarcinoma, like the EGJA association that we report here, was found to be independent of H pylori.
In a previous analysis from the ATBC Study cohort, we reported that H pylori
infection was statistically significantly inversely associated with adenocarcinomas of the esophagogastric junction (referred to as gastric cardia adenocarcinomas in that report) (OR = 0.31, 95% CI = 0.11 to 0.89) and was a statistically significant risk factor for GNCA (OR = 7.9, 95% CI = 3.0 to 20.9) (6
). In contrast to this striking difference in H pylori
association, in the current analysis, both low serum pepsinogen I and low serum ghrelin were statistically significantly associated with increased risk of adenocarcinoma at both sites, suggesting that the carcinogenic effect of H pylori
may not always be mediated by gastric fundic atrophy, at least in the esophagogastric junctional region.
Like ghrelin, the proenzyme pepsinogen I, is also produced in the gastric fundic mucosa. Pepsinogen I is commonly used to serologically indicate the presence of gastric fundic atrophy, the destruction of the fundic glands and frequent sequelae of chronic inflammation, and it has been investigated as a possible early detection marker for gastric cancer (24
). Gastric fundic atrophy also results in destruction of the ghrelin-producing cells in the fundic mucosa (1
), so ghrelin may be a marker worth investigating for its potential in identifying early gastric cancer.
Our analysis suggests, however, that ghrelin and pepsinogen may act differently in the context of upper gastrointestinal carcinogenesis. When risk was calculated by time from baseline to the development of cancer, the increase in risk of GNCA and EGJA associated with low baseline serum pepsinogen I was confined to those cancers occurring within 5 years of baseline, indicating that serum pepsinogen I may be altered only in the latter stages of carcinogenesis. Similar temporal associations between serum pepsinogen I and gastric cancer have been previously noted (26
). In contrast, the increase in risk of GNCA and EGJA associated with low baseline serum ghrelin remained statistically significant for cancers occurring long after baseline, indicating that changes in serum ghrelin may occur early in the carcinogenic process, long before the development of the tumor, and that ghrelin may be involved in the etiology of these upper gastrointestinal cancers.
The potential role of ghrelin in carcinogenesis is not yet known; however, data regarding ghrelin’s relevance to both inflammation and carcinogenesis have been reported. The relationship between ghrelin and inflammation preceding atrophy is likely complex: Whereas most studies report that ghrelin has predominantly anti-inflammatory associations (2
), there are also data to suggest that ghrelin may be associated with increased inflammation in some situations (2
). In a study of plasma ghrelin levels across various gastrointestinal disorders, the lowest ghrelin levels were associated with chronic gastritis, whereas the highest levels of ghrelin were seen in patients with acute gastritis and patients with gastric cancer (31
). Higher circulating ghrelin levels among cancer patients may be the result of a compensatory response, possibly involving secretion of ghrelin from auxiliary ghrelin-producing organs (such as the small and large intestines, the kidney, or the lung); however, the mechanism and function of such a response, if it occurs, are unknown (13
The relationship between ghrelin and carcinogenesis appears similarly complicated. Colorectal carcinoma cells are reported to secrete excessive ghrelin in vitro, and in these cells, ghrelin appears to act in both an autocrine and a paracrine manner to promote the proliferative and invasive nature of the cells (34
). An increase in proliferation in response to secreted ghrelin has also been observed in human pancreatic and hepatoma cell lines (35
). However, studies of human thyroid, breast, and prostate cancer cell lines have shown that ghrelin induces both proliferative and antiproliferative effects, which are often dependent on the histological cell type and the dose and timing of ghrelin administration (30
). Further studies are needed to characterize the interaction between ghrelin, inflammation, and carcinogenesis in different organs.
The prospective design of our study is one of its major strengths because baseline prediagnostic serum for analysis of ghrelin, H pylori infection, and pepsinogen I was collected for analyses. The ATBC Study also includes substantial covariable information that allowed for adjustment for potential confounders.
The ATBC Study includes only male smokers, and as such, the generalizability of our findings may be limited. Unfortunately, data regarding serum pepsinogen II serostatus was unavailable in this analysis, thus preventing the use of both low pepsinogen I levels and low pepsinogen I/II ratio as indicators of gastric atrophy. H pylori CagA serostatus, a marker of H pylori infection virulence, was also unavailable, although the data indicate that H pylori infection did not substantially modulate the risk associated with low ghrelin. As with all epidemiological studies, the possibility of residual confounding cannot be excluded.
In conclusion, in this large prospective study, we found that individuals with lower baseline serum concentrations of ghrelin had a statistically significant increase in the risk of both GNCA and EGJA. Serum ghrelin levels may be a useful marker of gastric fundic atrophy and may also have a role in the etiology of gastric and esophagogastric junctional cancers. The gastrointestinal tract can be thought of as an endocrine organ, and further studies investigating the effects of alterations in the hormonal milieu of the stomach in response to H pylori infection and subsequent atrophy that could drive gastric carcinogenesis are needed.