In this case-cohort study, we prospectively evaluated the association between gastric fundic atrophy, as estimated by baseline serum pepsinogen levels, and future development of gastric and esophageal cancers in the General Population Nutrition Intervention Trial cohort in Linxian, China. We found an association between low serum PGI or PGI/II ratio and subsequent risk of gastric noncardia and cardia adenocarcinomas, but little evidence of an association between these markers and increased risk of ESCC. This is the largest evaluation to date of the association of gastric atrophy and gastric cardia adenocarcinoma, and it is the first prospective evaluation of the association of gastric atrophy and esophageal squamous cell carcinoma.
Most previous studies of the association between serum pepsinogens and gastric or esophageal cancer risk have used dichotomous comparisons based on single cut points, generally PG1 ≤70-30, PGI/II <3, or a combination of these cut points.[6
] We tested different PGI/II ratio cut points because of the relatively high median pepsinogen levels in our population. Higher serum pepsinogen concentrations have also been reported in other Asian populations.[6
] But in our quartile analyses () and nonlinear continuous analyses () we found no evidence of thresholds or logical cut points. Indeed, our results suggest that dichotomous comparisons are not an efficient use of data in estimating associations between serum pepsinogen concentrations and risk of gastric cancer and that these comparisons may be misleading because any cut point will collapse people at considerably dissimilar risk into the same category.
Another interesting finding in this study was the strong correlation found between PGI and PGII (Pearson’s r = 0.67). Previous studies have also found similar strong correlation coefficients between PGI and PGII [3
], perhaps because both peptides are secreted by the fundic cells of the stomach. These finding are consistent with the hypothesis that the PGI/II ratio takes into account both the fact of fundic atrophy (via the PGI component) and the total secretion capacity of pepsinogens in an individual (via the PGII component).
Previous studies have consistently shown that low serum PGI or a low serum PGI/II ratio are associated with higher risk of gastric noncardia cancer.[31
] Our findings concur with these previous results. Also similar to most previous studies, we found that the PGI/II ratio was a stronger predictor of risk than PGI alone, even in models adjusted for H. pylori
There are few previous studies on the association of serum PGI or the PGI/II ratio with gastric cardia adenocarcinoma. Most previous prospective studies have had very limited numbers of gastric cardia cancer cases, so they have not reported pepsinogen data separately for cardia cancers.[16
] Some prospective studies, however, with moderate numbers of cardia cancer cases (ranging between 23 and 44), have reported on these associations, and all of these studies have shown increased cancer risk among subjects with low serum PGI or PGI/II ratios, with relative risks (95% CI) of 5.0 (0.6 – 42.8) [15
], 4.11 (1.42 – 11.9) [18
], and 1.60 (0.62 – 4.14).[28
] Likewise, three case-control studies that examined these same associations all found increased risk of gastric cardia cancer associated with low serum PGI or PGI/II values.[7
] Of note, all studies reporting the magnitude of the association for both sites have found similar odds ratios for cardia and noncardia cancers. Our results confirm these previous findings, and show that gastric atrophy increases risk of both cardia and noncardia gastric cancers in Linxian, with similar magnitudes and association patterns at these two cancer sites.
Two recent studies, one from Norway [28
] and one from Iran [32
], showed that the risk of cardia cancer associated with atrophy may be modified by H. pylori
status. However, our results did not show any statistically significant interaction between atrophy and H. pylori
in causing cardia cancer. Also, another study from Japan suggested that risk of gastric cancer was highest in those who had atrophy but were seronegative for H. pylori
] In contrast, in our study, the highest risks were observed among those who had atrophy and were seropositive for H. pylori
antibodies. These differences in results may be related to chance findings because of small sample sizes or may be due to differences between study populations. The numbers of cardia cancer cases in the Norweigan and Iranian studies were 44 and 53, respectively. Also, the total number of gastric cancer cases in the Japanese study was 43. In our study area the cardia cancer rates are unusually high and are a large proportion of gastric cancer cases (approximately 75% of all gastric cancers); cardia cancer co-occurs with the very high rates of ESCC; and the risk of cardia cancer is increased among those who are seropositive for H. pylori
] Therefore, population-specific findings for cardia cancer are also possible.
Ye and colleagues, in a case-control study published in 2004, were the first to report an association between low serum pepsinogen levels and ESCC risk [7
], and others have since reported that an association is present in Japanese [21
] and Dutch populations.[23
] When we analyzed our data dichotomously, we also found a borderline insignificantly increased risk of ESCC associated with low serum PGI/II ratio. But, unlike the associations seen with gastric cardia and noncardia cancer, there was no evidence of an increasing trend in HRs across the exposure quartiles and no evidence of an association in nonlinear continuous models. When we stratified on follow-up time it showed an apparently stronger association with ESCC in the first 5.25 years of follow-up (the trial intervention period) than in the subsequent 10 years of follow-up. de Vries et al
. reported a similar phenomenon in their cohort.[23
] The Dutch study investigators attribute their result to selection bias, but this can’t be the explanation in our study design. Overall, our prospective study finds little evidence of an association between serologic markers of gastric atrophy and ESCC. But, we note that in a separate analysis using a different group of subjects in Linxian, we found a strong linear association between serum PGI/II ratio and risk of esophageal squamous dysplasia, the precursor lesion for ESCC.[30
We believe that our findings suggest that pepsinogen concentrations alone will not be useful for cancer screening. Low serum PGI and PGI/II ratio levels predict higher risks of gastric cardia and noncardia cancers, and perhaps higher risk of ESCC as well, but as Stemmermann and colleagues have commented,[14
] these measurements are not sensitive enough to be used for screening. Low serum PGI and a low PGI/II ratio have been reported to be associated with 2-10 fold increased risk of gastric cancer, but successful screening techniques are usually associated with much larger relative risks.[33
] For example, a marker with a sensitivity and specificity of 95% has an odds ratio of 361. This is also reflected in the newest Japanese Guidelines for Gastric Cancer Screening that do not recommend serologic testing for serum pepsinogens.[34
The strengths of this study include its prospective design, a large sample size, essentially complete follow-up, modeling the associations using cut points, quartiles, and nonlinear continuous models, and the availability of data on potential confounders. Furthermore, our study was conducted in a population at high risk for the diseases in question, where the results are most relevant. The results may or may not be generalizable to Western populations, which have a lower incidence of these cancers and where cardia cancer may have a different etiology from those studied in Asian populations.[35
In summary, this prospective study confirmed a strong association between gastric fundic atrophy, as estimated by low serum PGI and PGI/II ratio, and subsequent risk of cardia and noncardia gastric cancers. There was little evidence of an association with an increased risk of ESCC.