The current study mainly reveals the role of eight serum trace elements in the development of gastric cancer. The results demonstrated strong inverse associations between serum concentrations of Se, Mo, Ca and risk of gastric cancer. Meanwhile, high serum concentrations of Cu and Cu/Zn ratio related to increased risk of gastric cancer. Although decreased risks of gastric cancer were also observed in higher serum level of Zn and Fe, no dose-response associations were found.
The data from the present study are consistent with the impression that high serum Se may be associated with decreased risk of gastric cancer. Previous studies have shown that Se may have anti-carcinogenic effects, especially against cancers of lung, prostate, skin and gastrointestinal system.(24, 25) One study observed significant lower serum levels of Se in esophageal cancer group, as compared with normal healthy controls.(26) A nutrition intervention trail conducted in Linxian County among general population observed lower mortality of gastric cancer in participant groups receiving supplementation with vitamins and minerals (including Se) than individuals who did not receive the supplements.(27) Of note, Linxian County is also a rural area with poor socioeconomic status and well-known for its high incidence of gastric cancer, which is very similar to the study region of the current study.(28) Furthermore, it worth mention that, the inverse association between Se level and gastric cancer may only occur in populations with low Se levels.(29) Serum level of Se below 70μg/L is usually considered as deficiency.(30) According to this standard, 25.4% of our controls (76/299) and 34.1% of all gastric cancer cases (102/299) were considered to be Se deficient. It could be inferred that low level of Se might contribute partly to high incidence of gastric cancer found in Xianyou County.
Essential elements Cu and Zn have a role in many biochemical reactions as a micro-source.(31) Zn alone has been associated with risk of gastric cancer, but the epidemiological finding have been quite limited and controversial. Zhang et al. have also observed higher serum concentration of Zn in gastric cancer cases than healthy controls.(12) However, a Japanese study found no excess risk of gastric cancer among those with the lowest levels of Zn (OR=1.2).(13) Although in our study, decreased risks of gastric cancer were found in the third quartile of serum Zn, the linear association was not statistically significant. On the other hand, higher level of Cu was also observed associated with higher risk of gastric cancer in the current study. Our result is partly supported by previous studies which detected higher level of Cu in gastric cancer cases in compared to health controls.(32) It has been known that Cu participates in the reductive activation of H2O2, causing damage to cellular DNA, proteins and lipids. The interaction of H2O2 with Cu generates more reactive oxygen species, such as hydroxyl radicals. These reactive oxygen species have been considered as being responsible for the process of carcinogenesis.(33) More importantly, our results demonstrated that high Cu/Zn ratio could be a strong risk factor of gastric cancer. Disturbances of blood Zn and Cu concentrations have been previously observed in many types of cancers including head and neck, gastrointestinal, and bladder carcinomas, and the Cu/Zn ratio was also suggested as a biochemical marker of cancer prognosis.(32, 34-37)
Our results found limited evidences for the association between serum Fe status and GCC and all gastric cancer combined, which is partly consistent with those from previous studies. In the European Prospective Investigation into Cancer and Nutrition (EPIC) study, inverse dose-response associations were found between serum Fe and overall risk of gastric cancer (OR4th vs. 1st quartile=0.62, 95% CI: 0.44-0.88, p for trend=0.034), as well as NCGC (OR4th vs. 1st quartile=0.54, 95% CI: 0.33-0.89, p for trend=0.029).(38) Similarly, a Finnish men cohort study also found serum Fe had an inverse, or possibly “u” shaped relationship with this malignancy in the NCGC site (OR3rd vs. 1st quartile =0.39, 95% CI: 0.19-0.78, p for trend=0.06), although the trend analysis was not statistically significant.(38) In another Finnish cohort study, which involved 120 incident male gastric cancers and 76 female gastric cancers, the relationship in males was statistically significant (RR4th vs. 1st quartile=0.60, p for trend<0.01).(39)
The present study also observed lower risk of gastric cancer, regardless of GCC or NCGC, in the higher quartile of serum Mo, indicating the protective role of Mo in the development of these diseases. However, little evidence exists to explain the effects of serum Mo on gastric cancer. An earlier Chinese study showed that serum Mo levels of 33 patients with gastric cancer were significantly lower than those of 77 healthy controls.(20) Similarly, a recent published Chinese study found that serum Mo concentration tended to be lower in H.pylori-infected participants than those un-infected, although no statistically significant differences were actually observed.(40) Due to the scare epidemiological data, the appropriate amount of serum Mo in human warrants further investigations.
Extensive epidemiological evidence has indicated the protective role of dietary calcium or Vitamin D against gastrointestinal cancer, including gastric cancer.(41, 42) However, how serum calcium influence gastric cancer remains indefinite. A large scale Swedish cohort study evaluated serum calcium status in 782 incident gastric cancers.(43) Although lower ORs were observed in the higher quartiles of serum calcium, no statistically significant association was found.
Some methodological issues of our study deserve attention. The strengths include the large sample size; individual matching for age, sex and resident region by gastric cancer risk; the standardized tumor classification; the personal interviews with all study participants in a standard and strict manner; and stratified analysis by different gastric cancer localization. Meanwhile, our study has some limitations that should be described. A major concern is that we were not able to adjust to H. pyloric infection, which might potentially cause confounding effect on the association between serum trace elements and gastric cancer, especially NCGC. However, the availability of chronic atrophic gastritis help to reduce the potential confounding effect, as H. pyloric infection was believed to cause NCGC through causing gastritis and gastric atrophy. (44) Another concern is the possibility of exposure misclassification using a questionnaire that has not been validated. However, the reliability rate of our questionnaire was estimated as high as 97%, suggesting the potential of high accuracy in measuring risk factors (data not shown). Thirdly,the serum level of trace elements based on one single blood sample might also cause some information bias.Further study could be guaranteed by collecting several blood samples at different time points within a day, or different seasons within a year, and using average level as there true level of serum trace element. Finally, we were not able to adjust to types of medication taken in the past one month. Use of several types of medicines have been observed to influence the serum trace element. For example, earlier study demonstrated that statin treatment was associated with a significant reduction in mean serum Zn (9%, p=0.03) and Cu (9%, p<0.01).(45)Although we did ask participants about type of medication taken in the past months, only 8 cardia patients, 3 noncardia patients , and 73 controls provided details. Due to the limited responses, we were notable to adjust medication use in the analysis. Further study is warranted with more details of medication taken prior the data collection.