In our study, we did not observe an increased risk of colorectal cancer with atrophic gastritis. We assessed atrophic gastritis both biochemically with SPGI as a biomarker, and histopathologically, but we did not observe an increased risk using either modality of assessment. The subjects in our study were 50–69 years-old when they were enrolled in the ATBC trial and were followed up for duration up to 17 years (mean of 11.3 years) after determination of atrophic gastritis. Our follow-up duration was adequate for a large number of cases to be identified and yet, we did not find any suggestion of a positive association.
To the best of our knowledge, there is no previous prospective cohort study that has evaluated the relationship between atrophic gastritis and colorectal cancer for us to compare our findings with. Only one case-control study has evaluated the relationship between atrophic gastritis and colorectal cancer risk. 4
In that study, 113 cases of colorectal cancer and 226 control participants who were enrolled in a health check-up program in Japan had serum pepsinogen, gastrin and Helicobacter pylori
antibody measured. The authors reported no association between Helicobacter pylori
infection, serum gastrin level or serum pepsinogen level with colorectal cancer.
Other studies have also evaluated factors related to atrophic gastritis and risk of colorectal cancer. 2–5, 9–12
Previous studies examining the association of Helicobacter pylori
with colorectal cancer found inconsistent results with some reporting positive associations 2,3
while others did not.4,5
In their study involving 384 subjects with colorectal cancer and 467 matched controls, Zumkeller et al. 3
reported a higher Helicobacter pylori
cases than controls (51% versus 44%), and a positive association between Helicobacter pylori
infection and colorectal adenocarcinoma (OR=1.41; 95%CI:1.06–1.87). In contrast, Limburg et al. 5
reported a lack of an association between Helicobacter pylori
infection and colorectal cancer risk in a case-control study nested within the ATBC cohort. In that study the serum of 118 cases of colorectal cancer patients and 236 matched controls was assayed for both Helicobacter pylori
whole cell and Helicobacter pylori
CagA antibodies. There were no differences in the seropositivity results between cases and controls: whole cell (OR=1.05; 95%CI: 0.63–1.74), cagA+ (OR=1.17; 95%CI: 0.74–1.84), and total Helicobacter pylori
seropositivity (OR=0.91; 95%CI: 0.53–1.55). Also, no significant association between proton pump inhibitor use and colorectal cancer was found in recent studies. 9–12
Robertson et al. 30
recently evaluated the association between pre-diagnostic serum gastrin level, Helicobacter pylori
seropositivity and the risk of recurrent colorectal adenoma using stored sera from two completed chemoprevention trials. The authors reported no association between serum gastrin level and risk of adenoma recurrence (RR=1.10; 95%CI: 0.78–1.54) and advanced adenoma recurrence (RR=0.82; 95%CI: 0.33–2.03), but a reduced risk of adenoma recurrence was observed with Helicobacter pylori
seropositivity (RR=0.76; 95%CI: 0.60–0.96) within 3 years of follow-up. This suggests that factors related to atrophic gastritis are not associated with colorectal carcinogenesis even at the early stages of adenoma formation and progression.
Studies have shown that countries with high gastric cancer typically have lower colorectal cancer incidence. 31
Finland, at least in the past, was a country with high risk of gastric cancer and low risk of colorectal cancer. 31
The reasons for this inverse ecological association are not well understood, but several speculative theories could be considered. Gastric cancer is usually seen in populations with lower socio-economic status, perhaps because of higher rates of Helicobacter pylori
infection, food handling practices and dietary patterns such as heavy consumption of salted and smoke-dried foods. 32–34
In contrast, colorectal cancer is seen more often in higher socioeconomic groups, perhaps due to obesity and less physical activity. It is also quite possible that changes in the gastric micro-environment may be contributing to this inverse ecological association and would merit further research. Nonetheless, it appears that factors that predispose to gastric cancer may not have the same effect in the colon.
Proton pump inhibitors are now very commonly used on a long-term basis in the United States and many other countries of the world. Our study provides some reassuring evidence, by extension, that long-term therapy with proton pump inhibitors, at least in adults, may not increase the risk of colorectal cancer through alteration of gastric homeostasis and perhaps gastrin-related mechanisms.
Potential strengths of our study are that our study population was from a large prospective study; data on risk factors were collected prospectively; dedicated trial pathologists examined the biopsy specimen; and atrophic gastritis was determined using both SPGI and histopathology. We also evaluated the association over a long follow-up period (up to a maximum of 17 years) after SPGI assays using incident colorectal cancer cases ascertained from an accurate cancer registry in a population with relatively low migration.
However, our study has many limitations. Participants in the ATBC were limited to Finnish male smokers which may affect the generalizability of our findings particularly to women and non-smokers, although most previous associations found in this cohort have been corroborated in other cohorts. We did not have any information on PPI therapy as it was not widely prescribed at the beginning of this cohort. We also did not measure serum gastrin levels to confirm hypergastrinemia nor did we perform gastroscopy on all subjects. Hence, it is possible that some subjects in the reference group may actually have had atrophic gastritis despite normal SPGI level, and some subjects may also develop atrophic gastritis during the follow-up period. This may bias our results towards null. However, in a population - based study from Finland, 20
SPGI level was < 25 µg/l in 80% of subjects with severe atrophic corpus gastritis, but in only 2.1% of those without atrophic gastritis. Therefore, we estimate that the effect of such misclassification is minimal. There is also a possibility that participants with atrophic gastritis may modify their behavior which may in turn modify their risk of colorectal cancer. Unfortunately, we could not assess this possibility objectively in our study. However, there was no meaningful difference in the association between atrophic gastritis and colorectal cancer when we excluded participants with gastric dysplasia or malignancy (who are more likely to have lifestyle modification based on the severity of their gastroscopy findings) in sensitivity analysis.
In conclusion, our prospective long-term study did not demonstrate an increased risk of colorectal cancer with atrophic gastritis among Finnish male smokers. Our study suggests that factors which predispose to the development of atrophic gastritis may not increase the risk of colorectal cancer through direct effect on gastric homeostasis.