Iron status and gastric cancer risk in the EPIC-EURGAST study

  • Topic: Stomach cancer
  • Institution: Instituto Catalan de Oncología (ICO)
  • Country: Spain
  • Status: Completed

Scientific abstract

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Background

Although it appears biologically plausible for iron to be associated with gastric carcinogenesis, the evidence is insufficient. Experimental studies on the carcinogenic effect of iron in animal models, and epidemiological evidence suggest an association between excess iron intake and increased risk of some types of cancer. However, the evidence regarding gastric cancer is so far only indirect. Studies from our group have shown a relation between meat and non-cardia gastric cancer risk. There is also an association between red meat consumption that may be due to haem iron. Although dietary iron intake may be a good indicator of iron exposure in the gastrointestinal tract, it is not a marker of the body iron status. The latter can be determined by measuring levels of total iron, Transferrin and Ferritin in blood. Hepcidin provides information on the regulation of iron homeostasis. Furthermore, iron status and iron overload can be determined, at least in part, by variation in relevant genes.

Aims & Objectives

To further investigate the relationship between body iron status and gastric cancer risk.

The general hypothesis to be tested in our study is whether high iron exposure is associated with increased risk of gastric cancer. More specifically we hypothesize that: (a) high exposure to iron from diet, overall or specifically haem iron, is associated with increased GC risk; (b) moderate or high iron overload, as measured by markers of boy iron status and homeostasis is associated with increased GC risk; (c) genetic variations (mutations, CNVs) in genes related with iron homeostasis or overload are associated with increased GC risk.

How the study was carried out

We conducted a nested case–control study in the multi-centric EPIC study. The study included gastric adenocarcinoma cases and their corresponding controls that occurred during an average of 11 years of follow-up. We measured pre-diagnostic serum iron, ferritin, transferrin and C-reactive protein, and further estimated total iron-binding capacity (TIBC) and transferrin saturation (TS). Also, we measured hepcidin by HPLC. Moreover, we further researched the possible mediating effect of ferritin in the association of hepcidin with gastric cancer risk by applying mediation analysis technique.

Key findings & conclusions

In summary, our results showed a decreased risk of gastric cancer related to higher body iron stores as measured by serum iron and ferritin. Moreover, we found pre-diagnostic hepcidin concentrations to be inversely associated with subsequent gastric adenocarcinoma risk and it seems that such associations are in part mediated by ferritin. Considering the dominant mediating effect of ferritin and the previous findings we reported on biomarkers of iron status and adenocarcinoma risk, the inverse associations found in this study could also be due to bleeding from early gastric cancer lesions. Our results suggest that H63D variant in HFE gene seems to be associated with GC risk of the non-cardia region and intestinal type. Further investigation is needed to clarify the role of iron in gastric carcinogenesis and to better elucidate the possible direct and indirect effect of hepcidin in gastric cancer risk, preferably using a large prospective study design. 

Plain language abstract

Background

Although it appears biologically plausible for iron to be associated with stomach cancer, the evidence is insufficient to lead to any conclusions. Experimental studies evidence a cancer causing effect of iron in animal models, and epidemiological evidence suggest an association between excess iron intake or iron overload and increased risk of some types of cancer. However, the evidence regarding stomach cancer is so far only indirect. Studies from our group have shown a relation between meat and non-cardia stomach cancer risk. There is also an association between red meat consumption, maybe due to haem iron.

Although dietary iron intake may be a good indicator of iron exposure in the gastrointestinal tract, it is not a marker of the body iron status. The latter can be determined by measuring levels of total iron in blood, while Hepcidin in the plasma provides information on the regulation of iron homeostasis. Furthermore, iron status and iron overload can be determined, at least in part, by variation in relevant genes.

Aims & objectives

To further investigate the relationship between body iron status and stomach cancer risk. Our study tests whether high iron exposure is associated with increased risk of stomach cancer. More specifically we hypothesized that some dietary and genetic factors explain this association.

How the study was carried out

We conducted a case–control study within the multi-centric European Prospective Investigation into Cancer and Nutrition (EPIC) study. The study included stomach adenocarcinoma cases and their corresponding controls that occurred during an average of 11 years of follow-up. We measured pre-diagnostic serum iron, ferritin, transferrin and C-reactive protein, and further estimated total iron-binding capacity (TIBC) and transferrin saturation (TS). Also, we measured hepcidin by High Performance Liquid Chromatography (HPLC).

Key findings & conclusions

In summary, our results showed a decreased risk of stomach cancer related to higher body iron stores as measured by serum iron and ferritin. Moreover, we found pre-diagnostic hepcidin concentrations to be inversely associated with subsequent stomach adenocarcinoma risk. Further investigation is needed to clarify the role of iron in stomach carcinogenesis and to better elucidate the possible direct and indirect effect of hepcidin in stomach cancer risk, preferably using a large prospective study design.

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