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Department of Preventive Medicine, University of Southern California, Los Angeles, California 90089-9175
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In recent years, the role of soybeans in the etiology of stomach cancer has also been of considerable interest (3) . Soybeans are an abundant source of isoflavones (4) . Although many investigators have focused on the antiestrogenic properties of isoflavones in possibly preventing hormonally mediated cancers (5) , isoflavones are antioxidants (6) and possess other antitumor activities, including inhibition of angiogenesis (7) , topoisomerase (8) , and tyrosine kinase (9) . In in vitro studies inhibition of the cell growth of stomach cancer cell lines by genistein has also been reported (10) . Thus, high intake of soyfoods may reduce the risk of nonhormonally dependent cancers as well as hormonally dependent cancers.
There are two main categories of traditional soyfoods: nonfermented and fermented soyfoods. The main nonfermented soyfoods include soymilk, tofu (bean curd), soybeans, and soynuts; they are consumed mainly for nourishment. The main fermented soyfoods include soy paste (miso in Japan) and fermented soybeans (natto in Japan); fermented soy pastes are generally used as condiments in cooking or making soups, whereas fermented soybeans are also consumed as part of the meal (11) . Fermented soy paste is generally high in salt content (11) . In a review of soy and cancer, Messina et al. (3) suggested that there was an inconsistent relationship between intake of soyfood and stomach cancer; the risk seemed to increase with intake of fermented soyfoods (mainly miso) and decrease with intake of nonfermented soyfoods (mainly tofu).
We have conducted a quantitative review of published studies of the association of fermented and nonfermented soyfoods and stomach cancer. Our analysis shows, in agreement with the conclusions of Messina et al. (3) , that the "crude" (unadjusted) data suggest that high intake of fermented soyfoods increases the risk of stomach cancer, whereas high intake of nonfermented soyfoods lowers the risk. However, further analysis shows that fermented and nonfermented soyfoods may be correlated with salt and fruit/vegetable intake, respectively, that are themselves directly associated with stomach cancer risk (12) . The respective roles of salt, N-nitroso compounds, fruit/vegetable intake, and other dietary factors have not been adjusted for in the majority of the studies on soyfoods. The apparent effects of soy on stomach cancer risk may be simply due to these associations with actual causal factors. Our results emphasize that careful adjustment of potential confounders is critical in the evaluation of the role of soyfoods in the etiology of stomach and other cancers.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, whereas intake of nonfermented soyfoods was investigated in 2 of the
cohort (16
, 24)
and 9 (14
, 15
, 17 , 18
, 20, 21, 22, 23
, 26)
of the case-control studies (Table 2)
. Relevant information regarding each of the studies [i.e.,
study design, sample size (i.e., number of cases and
controls, if applicable), years of follow-up or study, source of the
cohort or cases and controls, and percentage of histologically
confirmed stomach cancers] is shown (Tables 1
and 2)
. With the
exception of three case-control studies that were population based
(20, 21, 22)
, the studies were hospital based with other
hospital patients as the control group. However, two hospital-based
case-control studies included a population-based group, as well as a
hospital control group (17
, 28)
. The extent of
histological confirmation of stomach cancer was not provided for the
cohort studies, including one conducted in Korea (24)
or
two conducted in Japan in which stomach cancer deaths were identified
from death certificates (13
, 30)
. For three other cohort
studies [one in Japan (33)
and two among
Japanese-Americans (16
, 32)
], the extent of histological
confirmation is likely to be high because incident stomach cancers were
identified by linkage with the tumor registries covering these study
areas. Among the case-control studies, the percentage of histologically
confirmed stomach cancer was 100% or nearly 100% in eight studies
(14
, 17, 18, 19
, 22
, 23 , 26
, 29)
, 52–88% in three studies
(20
, 21
, 28)
, and was not specified in three other studies
(15
, 25
, 31)
.
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and 2)
.
Statistical Analysis.
In our meta-analysis, we examined separately the influence of fermented
(miso, fermented soybeans, and soybean paste; Table 1
) and nonfermented
(tofu, soymilk, and processed tofu products) soyfoods (Table 2)
on the
risk of stomach cancer. For the pooled analysis, we took the reported
point estimate and SE of the log OR/RR (calculated from results
presented in the report or obtained from investigators, such as 95%
CIs) associated with the highest versus the lowest level of
soy intake for each study. A pooled estimate was calculated using a
fixed effects model in which the effect measures are log ORs/RRs
weighted by the inverse of the variance of the log OR/RR, giving larger
studies greater weight in the summary measure. All reported
Ps were derived from two-sided statistical tests.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Three studies (13
, 28
, 29)
found that high (at
least daily) intake of miso was associated with a lower risk of stomach
cancer (ORs/RRs ranged from 0.58–0.86); the result was statistically
significant in one study (13)
. In four other studies
(16
, 18
, 29
, 30)
, risk of stomach cancer was weakly or not
associated with intake of miso (ORs/RRs were between 0.90 and 1.04).
However, in 10 other studies, high intake of fermented soyfoods was
associated with an increased risk of stomach cancer; ORs/RRs ranged
from 1.2–10.3. The increased risk was statistically significant in six
of the studies (17
, 19
, 23
, 25
, 26
, 31)
. When we included
all 15 studies in a meta-analysis, the pooled OR/RR for high intake of
miso was 0.90 (95% CI, 0.86–0.94). This apparent inverse association
was mainly due to the reduced risk observed in the very large cohort
study of Hirayama (13)
that included over 5200 stomach
cancers (or some 65% of the cancers included in the pooled analysis).
When we excluded results from this one study, the pooled estimate based
on the other 14 studies was 1.26 (95% CI, 1.11–1.43). When we further
excluded the other most extreme study [i.e., the study by
Crane et al. (25)
, which found a 10-fold
increased risk associated with high soybean paste intake], the pooled
estimate was reduced slightly (OR/RR, 1.21; 95% CI, 1.07–1.38), but
it remained statistically significant. We also calculated a pooled
estimate of risk separately for cohort and case-control studies. The
pooled estimate was 1.13 (95% CI, 0.85–1.49) for cohort studies
[Refs. 16
, 30
, 32
, and 33
; excluding
Hirayama (13)
] and 1.30 (95% CI, 1.13–1.50) for
case-control studies (15
, 17, 18, 19
, 23
, 25
, 26
, 28
, 29
, 31)
.
Table 2
summarizes the studies with data on nonfermented soyfoods and
risk of stomach cancer, separately for cohort and case-control studies
(the studies are ordered by decreasing magnitude of the OR/RR). One
study showed an increased risk of stomach cancer in association with
high tofu intake (15)
, and another showed no association
between intake of soybean milk and risk (23)
. A reduced
risk ranging from 0.2–0.89 was found in the other 10 studies; results
were statistically significant in 4 of these (20, 21, 22
, 26)
.
When we conducted a meta-analysis, the OR/RR for high intake of
nonfermented soyfood was 0.72 [95% CI, 0.63–0.82; the OR of 0.69
found by Haenszel et al. (14)
was not included
in this meta-analysis because a SE was not presented in the report and
could not be calculated]. A reduced risk was observed for both cohort
and case-control studies; the pooled estimate was 0.61 (95% CI,
0.38–0.98) for the cohort studies (16
, 24)
and 0.73 (95%
CI, 0.63–0.83) for the case-control studies (15
, 17
, 18
, 20, 21, 22, 23
, 26) .
Because miso and other fermented soyfoods may be a marker of salt
intake and nonfermented soyfoods may be a marker of plant food intake,
we also examined the risks associated with intake of salt and plant
food in the same studies reviewed in Tables 1
and 2
. Fig. 1
shows graphically the ORs/RRs associated with intake of fermented
soyfoods (left) and salty foods (right); these
ORs/RRs were unadjusted for each other. The last two columns
of Table 1
show for each study the specific salty food investigated,
definition of high and low levels of intake, and the corresponding risk
estimate comparing a high versus low level of intake.
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and Table 1
show that the risks for stomach
cancer associated with high intake of salt and miso generally follow a
similar pattern. Specifically, of the nine studies that found an
increased risk in association with high miso intake (OR/RR of 1.2 or
greater) and presented results on salt (salty food) intake, eight also
found an increased risk (OR/RR ranged from 1.3–12.4) in association
with such high salt intake. (The RR was 0.9 for males in one study;
Ref. 32
). Of the five studies in which high intake of miso
was inversely or not associated with an increased risk of stomach
cancer (OR/RR ranged from 0.58–1.04), high intake of salt (salty
foods) was associated with an increased risk in one study (males in
Ref. 29
; OR of 1.5) but not in four others (Refs.
16
, 18
, 28
, and females in Ref. 29
; OR/RR of
0.5–1.1). [Three of the studies in Table 1
did not present results
associated with salt (salty food) intake (13
, 19
, 30)
.]
Fig. 2
shows graphically the ORs/RRs associated with intake of nonfermented
soyfoods (left) and vegetable/fruit intake
(right); these ORs/RRs were unadjusted for each other. The
last two columns of Table 2
show for each study the specific
vegetable/fruit investigated, definition of high versus low
levels of intake, and the corresponding risk estimate comparing the
high versus the low level of intake.
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and Table 2
show that the risks for stomach
cancer associated with high intake of vegetables/fruits and
nonfermented soyfoods show remarkably similar patterns. In all of the
studies that found an inverse association between intake of
nonfermented soyfoods and stomach cancer risk (OR/RR of 0.89 or lower),
a reduced risk of stomach cancer was also reported in association with
high intake of total vegetables (14
, 20
, 21)
, specific
vegetables (17
, 18
, 22
, 26)
, or fruits (Ref.
16
; Table 2
). Of the two studies that found no association
between intake of nonfermented soyfoods and stomach cancer risk, one
found a reduced risk (23)
and the other an increased risk
in association with high intake of vegetables (15)
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. All but 1 (14)
of the 11 studies conducted in Japan or
among Japanese in Hawaii asked about intake of miso, whereas only 4 of
these studies also asked about intake of tofu (15, 16, 17, 18)
. Of
the five studies conducted among Chinese living in China or Taiwan, one
asked about fermented soybeans (19)
, three asked about all
soybean products combined (20, 21, 22)
, and one asked separate
questions regarding intake of soybean milk and fermented beans
(23)
. Of the three studies conducted in Korea, one asked
about tofu (24)
, one about soybean paste
(25)
, and one about intake of soybean paste and tofu
(26)
. Reasons for the finding of an inverse association between high miso intake and risk in the Japanese cohort study of Hirayama (13) , but an increased risk in most of the other cohort and case-control studies, are not apparent. Because of the divergent results and the large contribution of this single study to the pooled results, we conducted pooled analyses with and without the Hirayama (13) study.
Our pooled results suggest that soyfood may differentially affect the risk of stomach cancer, depending on whether it is fermented or nonfermented soyfood. Risk of stomach cancer decreased significantly in association with high intake of nonfermented soyfoods (including tofu, soybeans, and soymilk). However, high intake of fermented soyfoods (miso, fermented soybeans, and soybean paste) was associated with a statistically significant increased risk when we excluded the Hirayama study (13) . This result was reversed, and the pooled result suggested a decreased risk when the Hirayama study (13) was retained in the analysis.
Because fermented and nonfermented soyfoods may be markers of
other dietary factors that influence risk of stomach cancer, we
explored whether the presence of potential dietary confounders may
explain the observed results relating to fermented and nonfermented
soyfoods. We specifically investigated the role of salt and plant foods
because they have been shown to influence stomach cancer risk and
because risk estimates associated with these two groups of foods were
available in most of the studies included in this meta-analysis
(last column of Tables 1
and 2
). However, salt and plant
foods are only examples of potential dietary confounders in studies of
fermented and nonfermented soyfoods. Besides salt, other compounds such
as N-nitroso compounds may also contribute to the observed
association between fermented soy products and stomach cancer. Nine
studies presented any data on intake of N-nitroso compounds:
nitrate-containing foods (32)
, broiled fish (15
, 25
, 26
, 28
, 30)
, smoked foods (17
, 23)
, and
ham/bacon/sausage (16)
were asked. Although there was some
concordance between the ORs/RRs for foods rich in N-nitroso
compounds and fermented soyfoods, the data are too few to be confident
that such a relationship exists.
Our results do suggest concordance in the results between fermented
soyfoods and salt (Table 1
and Fig. 1
) and between nonfermented
soyfoods and plant foods (Table 2
and Fig. 2
), pointing to the
importance of considering these and other potential confounders (such
as N-nitroso compounds) in future studies. The results on
salt intake and stomach cancer are not totally consistent in the
studies included here; this is not surprising because of the
well-recognized difficulty in assessing total salt intake
(32)
. More importantly, the assessment of salt intake
varied in this group of studies; all salty foods combined, specific
high-salt food(s), salt, soy sauce, or salt preference were
investigated in the different studies. (Note that soy sauce is low in
isoflavone content; Ref. 34
.)
Of the studies reviewed, one investigated the joint associations of salt and soybean paste (26) . An increased risk of stomach cancer associated with high intake of soybean paste stew was present for those who preferred low, intermediate, or high amounts of table salt in their diet (26) . This (26) and another study (17) also offered some information on the association of fermented and nonfermented soyfoods in univariate and multivariate analyses when the two types of soyfoods and other dietary factors were considered simultaneously. In one study, the risk reduction associated with tofu intake was enhanced (OR was 0.3 in univariate analysis and 0.2 in multivariate analysis), and the increased risk associated with soybean paste was reduced (OR was 10.3 in univariate analysis and 5.5 in multivariate analysis; Ref. 26 ). In the multivariate analysis that included two soyfoods and seven other dietary factors, the decreased risks associated with vegetable intake (cabbage and spinach) and the increased risk associated with salt preference remained statistically significant (26) . A somewhat different picture emerged in another study (17) that examined simultaneously the association of salty foods, miso soup, soybean products (excluding miso), raw vegetables, green-yellow vegetables, and six other dietary factors on risk of stomach cancer. In this study, the OR associated with soybean products changed from 0.6 in a univariate analysis to 0.9 in a multivariate analysis; the respective ORs associated with high intake of fruits, green-yellow vegetables, and raw vegetables were 0.4, 0.5, and 0.4 in univariate analysis and 0.7, 0.8, and 0.5 in multivariate analysis. In contrast, high intake of miso and salty foods were significant risk factors in both univariate (respective ORs were 2.1 and 2.3) and multivariate (respective ORs were 1.9 and 2.2) analyses (17) . Thus, in this study, the increased risk associated with high intake of miso remained, whereas the decreased risk associated with high intake of nonfermented soyfoods was largely eliminated after adjustment for each other and other dietary factors including salty foods and vegetable intake. However, it cannot be determined from the multivariate results presented whether this change in OR associated with nonfermented soyfoods is due to the adjustment of miso, salt, a specific plant food, or a combination of these dietary factors (17) .
The question remains whether any conclusions can be reached regarding the role of nonfermented and fermented soyfoods in the etiology of stomach cancer. If we accept the pooled result (excluding the Hirayama study; Ref. 13 ) that fermented soyfoods increases the risk of stomach cancer, is this observation due to specific soy constituents or to the salt content, N-nitroso compounds, or other dietary components of fermented soyfoods? Is there any evidence that the increased risk associated with salt intake (at least in those studies conducted in populations in which soyfoods are consumed) may be confounded by intake of fermented soyfoods such as miso?
Although high intake of miso (17) and soybean paste (26) remained as significant risk factors when salt intake was considered in the two studies discussed above, additional data are needed to determine with certainty that high salt (or other dietary components) in fermented soyfoods is not the apparent explanation. We are not aware of specific soy constituents in fermented soyfoods that may have harmful effects on the gastric mucosa. Future studies need to better characterize not only intake of total salt and N-nitroso compounds, but also the contribution of fermented soyfoods to their total intake. With the availability of more precise information on these exposure variables, the separate and combined effects of fermented soyfoods, salt, and N-nitroso compounds on stomach cancer risk can be determined.
If we accept at face value the pooled result that high intake of nonfermented soyfoods decreases the risk of stomach cancer, is this observation due to the high intake of vegetables/fruits, specific antioxidants, or are there specific soy constituents in nonfermented soyfoods that may protect the gastric mucosa? Is there any reason to believe that the inverse association with high intake of vegetables/fruits may be "explained" by the associations of nonfermented soyfoods, at least in those populations in which soyfoods are consumed?
Various constituents of soyfoods (e.g., protease inhibitors, saponins, and isoflavones) may, in fact, lower the risk of stomach cancer (3) . The reduced risk associated with intake of nonfermented soyfoods remained in one study (26) but was largely eliminated in another (17) after adjustment for intake of fermented soyfoods, salt, and vegetables. More data are needed to firmly establish the role, if any, of nonfermented soyfoods and stomach cancer risk. It is important that future studies obtain information on intake of different types of nonfermented soyfoods so that analyses may be conducted by individual soyfoods (e.g., tofu, and soymilk) and for all nonfermented soyfoods combined. Results from both studies (17 , 26) suggest that it is unlikely that the inverse association with intake of fruits/vegetables may be explained by high intake of nonfermented soyfoods. Moreover, a decreased risk of stomach cancer in relation to high intake of fruits/vegetables has been reported in a large number of stomach cancer studies (primarily case-control design) conducted in both high- and low-risk populations worldwide.
In summary, the role of soyfoods in stomach cancer cannot be determined until the roles of potential confounders including intake of salt, N-nitroso compounds, plant foods, and other dietary factors are considered. Few of the published studies examined the independent effect of intake of fermented or nonfermented soyfoods after adjustment for other relevant dietary factors; this is clearly needed.
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Footnotes |
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1 Supported by Grant R01-CA080662 from the
National Cancer Institute. 
2 To whom requests for reprints should be
addressed, at Department of Preventive Medicine, University of Southern
California, 1441 Eastlake Avenue, MS #44, Los Angeles, CA 90089-9175.
Phone: (323) 865-0480; Fax: (323) 865-0139; E-mail: annawu{at}hsc.usc.edu
3 The abbreviations used are: CI, confidence
interval; OR, odds ratio; RR, relative risk.
Received 12/28/99; revised 7/26/00; accepted 8/14/00.
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References |
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