The results of this large, nested case–control study show that higher plasma concentrations of some individual carotenoids (β-cryptoxanthin, zeaxanthin), retinol and α-tocopherol are associated with a significant lower risk of developing GC during the follow-up period.
Carotenoids and tocopherols have been suggested to be cancer preventive mainly because of their antioxidant properties, which may lead to a reduction in the extent of oxidative stress, lipid peroxidation and DNA damage, whereas retinol, along with the provitamin A carotenoids, is involved in the control of cellular growth kinetics (Sporn and Roberts, 1983
). Despite this potential, results from previous reports on dietary intake of carotenoids assessed from dietary questionnaires have been mixed and many have not shown strong associations with GC risk (Chyou et al, 1990
; Zheng et al, 1995
; Botterweck et al, 2000b
). To date, only a few studies have considered prediagnostic blood levels of carotenoids in association with GC risk. A small Japanese study found no association between GC risk and blood levels of retinol, β
-carotene or α
-tocopherol, but did not consider anatomical subsite or histological subtype (Nomura et al, 1995
). Larger studies, set in high-risk Chinese populations, show either (i) a borderline significant negative association between retinol and GCs of the cardia, and between β
-cryptoxanthin and noncardial GC, and an increased risk of noncardial GC with higher levels of lutein/zeaxanthin (Abnet et al, 2003
) or (ii) an inverse effect of α
- and β
-carotene and lycopene on GC risk, but without consideration of anatomical subsite or histological subtypes (Yuan et al, 2004
Most of the current literature on carotenoids and GC risk is focused on β
-carotene (Correa et al, 1998
). This study did not observe any association with plasma levels of α
- or β
-carotene and GC risk, whereas previous prospective studies have shown lower plasma levels of β
-carotene in GC cancer cases vs
controls in a Western population (Eichholzer et al, 1996
) and either an inverse association (Yuan et al, 2004
), no association (Abnet et al, 2003
) or a positive association (You et al, 2000
) with GC risk in high-risk Chinese populations. Intervention studies with β
-carotene, however, have shown no effect on GC risk in low-risk populations (Hennekens et al, 1996
), and either no effect (Varis et al, 1998
) or mild protective effects in high-risk populations (Blot et al, 1995
; Correa et al, 2000
). In the present study, no GC risk associations were observed for dietary β
-carotene and in a concurrent study of fruit and vegetable intake based on the entire EPIC cohort, no GC risk association was observed with the intake of fruiting and root vegetables (Gonzalez et al, 2006
), which are good sources of carotenes (Al Delaimy et al, 2005a
). Taken together, these observations suggest that any protective effects of the carotenes, or carotenoids in general, are likely to be small.
The present study did not observe any statistically significant inverse associations with blood levels of lycopene, which is obtained predominantly from tomatoes and tomato-based products. Blood lycopene levels have previously been shown to be associated with an inverse GC risk (Yuan et al, 2004
), but this was in a high-risk Chinese population with low baseline lycopene levels. It may be that, given the higher tomato consumption in Western populations, both cases and controls in the present study were above a threshold of lycopene effect levels.
Dietary lutein, zeaxanthin and β
-cryptoxanthin, which belong to the xanthophyll family of carotenoids and are found mostly in corn, leafy green vegetables and citrus fruits, have been shown to have no association with GC risk in ecological (Tsubono et al, 1999
), case–control (Garcia-Closas et al, 1999
; Chen et al, 2002
) and cohort (Botterweck et al, 2000b
) studies. In a concurrent study of fruit and vegetable intake based on the entire EPIC cohort, a negative GC risk association was observed with the intake of citrus fruits, some members of which are good sources of these carotenoids (Gonzalez et al, 2006
). Only two studies to date, both in high-risk Chinese populations, have considered prediagnostic blood levels of these carotenoids. One (Yuan et al, 2004
) found no risk association, whereas the other (Abnet et al, 2003
) showed a significant increased risk of noncardial GC with high intake of lutein and zeaxanthin.
In general, retinol, which is mostly derived from animal sources, has not previously been associated with GC risk in a prospective setting (Abnet et al, 2003
; Yuan et al, 2004
; Nouraie et al, 2005
). However, in the present study, higher plasma retinol was associated with a lower risk of GC. Its potential involvement in important processes of carcinogenesis, namely cell differentiation, adhesion and membrane permeability (van Poppel and van den Berg, 1997
), imply that it may have a role in cancer prevention. Although these observations are encouraging, they require further confirmation and validation.
Previous results from prospective studies analysing blood α
-tocopherol levels are conflicting, probably because they are reflective of differences in the various populations analysed. For example, in different high-risk Chinese populations, higher blood α
-tocopherol has been shown to have either a nonstatistically significant (Yuan et al, 2004
) or borderline significant (You et al, 2000
) positive association with GC risk, or to be associated with a marginal decreased risk of cardial GC and an increased risk of noncardial GC (Taylor et al, 2003
). Conversely, in a Finnish population of smokers, higher baseline blood α
-tocopherol has been associated with a marginally significant increase in the risk of cardial GC (Nouraie et al, 2005
). In the present study, higher plasma α
-tocopherol level was negatively associated with GC risk.
It is also important to note that the plasma tocopherol results presented here are lipid-unadjusted. Some (Taylor et al, 2003
; Nouraie et al, 2005
) but not all (You et al, 2000
; Yuan et al, 2004
) of the above studies adjusted their blood tocopherol measures for blood total cholesterol in order to correct for possible confounding, as tocopherols are transported in the blood as part of lipoprotein complexes (Willett, 1998
). In the present study, this adjustment was not possible as data on blood total cholesterol values exist for only a subset of subjects. However, data on plasma total fatty acids and total saturated fatty acids do exist for all subjects. They may serve as surrogates for blood total cholesterol because, in the subset of subjects described above, blood total cholesterol was correlated with plasma total fatty acids (P
<0.001) and total saturated fatty acids (P
<0.001), whereas α
-tocopherol was correlated with plasma total fatty acids (P
<0.001), total saturated fatty acids (P
<0.001) and blood total cholesterol (P
<0.001), which is in line with previous observations (Willett et al, 1983
). Adjustments of plasma tocopherol measures for plasma total fatty acids or total saturated fatty acids did not materially alter the GC risk estimates obtained.
In the present study, no GC risk associations were observed for increasing dietary intakes of retinol and vitamin E, whereas their plasma measures showed significant negative GC risk associations in the highest quartiles. This observed difference in effect may suggest inaccuracies in the measured dietary values, perhaps owing to measurement errors in assessment of intake, errors in food composition tables or the lack of information on intake from dietary supplements. However, it is also true that measures of dietary intake, no matter how accurate, do not reflect the bioavailability of the nutrients from various foods, the level of absorption from the digestive tract or individual metabolising differences, which are key in determining blood concentrations of these nutrients. These results highlight the importance of measuring blood biomarkers of intake in addition to dietary intake levels.
The key advantage of the present study, aside from its prospective design, is its ability to differentiate GCs by anatomical subsite and histological subtype according to classifications made by a team of expert pathologists. Of the previous studies, all of them case–control, that have considered GC pathology in relation to dietary carotenoids, some have failed to detect any associations or differences by subtype (Boeing et al, 1991
; Buiatti et al, 1991
), whereas others have shown mixed results (Gonzalez et al, 1994
; Harrison et al, 1997
; Ekstrom et al, 2000
), suggesting that the effects of carotenoids might be similar in both histological subtypes. In the present study, none of the analytes, with the possible exception of α
-tocopherol, showed any significant effects by anatomical subsite or histological subtype. As data from previous prospective studies on the effect of these analytes on groupings of subsite and subtype are scarce, and the present findings are based on a small number of cases, confirmation with better-powered studies is necessary.
One of the key limitations of the present study may be the relatively short follow-up time. Cases identified within a short period after the start of the study may have suffered from some symptoms, leading to dietary changes and hence alterations in the blood carotenoid levels. In order to assess this, interaction tests were run to determine if an effect modification existed with follow-up time less than or equal to 2 years vs more than 2 years – none was found for any of the analytes. This may suggest that in this study, cases diagnosed close to study entry were not different from those diagnosed later. However, given the long-term nature of GC development and the relatively short follow-up time, some caution is necessary in the interpretation of the results of the present study. Another shortfall of this study is that the variable for total carotenoids was estimated as a simple sum of all carotenoid concentrations and thus does not account for factors such as differences in antioxidative activity or other similar factors that may affect their relative effects.
positivity is a major GC risk factor for both the diffuse and intestinal histological subtypes (Parsonnet et al, 1991
; Hansson et al, 1993a
) and may alter systemic carotenoid levels or their secretion patterns into the gastric juice (Zhang et al, 2000
; Annibale et al, 2002
). In this study, no effect modification by Hp status at baseline was observed, either because there is no such modification or owing to the fact that a large percentage of cases and controls were Hp positive. Although the results, with the possible exception of α
-tocopherol, do not show a difference of effect based on Hp infection status, better powered studies are called for.
Gastric cancer is known to be one of the many tobacco-related cancers (Gonzalez et al, 2003
), which have collectively been shown to be modified by dietary β
-carotene intake and smoking status (Touvier et al, 2005
). However, in the present study, no interaction with GC risk was observed between smoking status and any of the analytes, including β
In summary, these results from the EPIC study show that plasma levels of some individual carotenoids, retinol and α-tocopherol are inversely associated with GC cancers, irrespective of Hp status. The protective associations observed were similar for the cardia and noncardia subsites, although the association for α-tocopherol may be stronger in the diffuse histological subtype than in the intestinal one. This study has been a comprehensive analysis of many analytes and outcomes. Even though there is reason, based on the antioxidant properties of carotenoids and tocopherols, and the role of retinol in cellular growth kinetics, to believe that the findings presented here may be real, scepticism is merited and a need exists for the confirmation of these results in other prospective settings.