In the NIH-AARP Diet and Health cohort, none of the investigated sugars were associated with increased risk of colorectal cancer or with any other potentially IGF-I-related cancer (i.e. breast, prostate, pancreatic or endometrial cancer). In gender-combined analyses, added sugars were positively associated with risk of esophageal adenocarcinoma; fructose, particularly added fructose, were associated with risk of small intestinal cancer, and all investigated sugars were related to increased risk of pleural cancer. Total sugars, fructose and added fructose intake were associated with decreased risk of all cancers only among men. In women, all investigated sugars were inversely associated with risk of ovarian cancer. The observed positive findings for some rare cancers, as well as inconsistency in results between genders suggest a possibility for some chance results. We discuss our findings in light of the existing prospective evidence; case-control studies were reviewed only if no prospective data were available. Comparison with other studies though remains problematic as some studies investigated sugars as foods and not as nutrients, examined dietary patterns or defined variables differently (e.g. free vs. total fructose).
We observed a strong positive association between intake of added sugars
and risk for esophageal adenocarcinoma
. In a recent ecological analysis in the U.S., the rise in esophageal adenocarcinoma strongly paralleled the rise in percentage of energy intake from corn syrup as well as obesity for the period from 1973 to 199721
. In our cohort, BMI was strongly associated with this type of malignancy22
, however, omitting BMI from the model did not change the risk estimate, suggesting an independent effect of added sugars
. The lack of statistical significance in normal weight participants, as well as in never smokers may have been due to low statistical power. Causes of the increasingly prevalent esophageal adenocarcinoma23
are largely unknown, and this finding provides an etiological clue for further investigation.
We observed more than 2-fold increase in risk for small intestine cancer
with high fructose, especially high added fructose
intake. An earlier case-control study suggested that sugars may be associated with small intestine adenocarcinoma, yet the assessment of sugars intake was crude, and based on sugars as foods24
. We had a limited number of cases (n = 135), thus when more are accrued, further analyses by histological type in ours as well as other cohorts are warranted.
We observed a particularly strong risk of pleural cancer
for all investigated sugars. Occupational and environmental exposures to asbestos are established risk factors25
, and little is known about the possible dietary etiology of this malignancy. Although we could not control for participants’ occupation, we adjusted for their educational level, given that low education in this cohort was a strong risk factor for pleural cancer26
. Occupation and education have been used interchangeably as proxy measures for socioeconomic status27
. In our cohort, education was strongly associated with added sugars
intake, but less so with total sugars. In addition, total and added sugars
had opposite trends for proportion of current smokers across quintiles of intake. Nonetheless, for both total and added sugars
, we observed robust risk estimates of a similar magnitude, suggesting that residual confounding from education or smoking may be an unlikely reason for these associations, although occupation still could not be entirely ruled out as a potential confounder.
In women, total sugars, added sugars
and added fructose
intakes were positively associated with risk of leukemia
, and high fructose intake was associated with increased risk of bladder cancer
. Although leukemia has been previously shown to be associated with obesity and the association was stronger in women than in men28
, in our cohort, BMI was not a mediator of the effect. The observed association with bladder cancer was somewhat consistent with results from two case-control studies that reported increased risk with intake of foods high in added sugars29,30
. However, for both leukemia and bladder cancer, the increased risk observed in the substitution model was no longer significant in the partition model. It may be that in the former, the increased risk occurred due to decreasing energy-contributing foods high in protective micronutrients and bioactive compounds, rather than increasing sugars intake.
All investigated sugars were inversely associated with risk of ovarian cancer
. Only one cohort has investigated the effect of sugars other than lactose on ovarian cancer and found a suggestion of an increased risk for total sugars among post-menopausal women31
. Ninety seven percent of the ovarian cancer cases in our cohort were post-menopausal. Few risk factors for ovarian cancer are known, thus, our findings may have been confounded by unknown factors or indicative of a dietary pattern.
In women, we also detected a decrease in risk of liver cancer
with high added fructose
intake, which may have been due to a chance or an unidentified confounder, given inconsistent results between men and women. An intriguing finding was the inverse association of added sucrose
and added fructose
with pancreatic cancer
risk in women, whereas there was a suggestion of an increased risk with fructose from fruit. Contrary to the methods used here, an earlier analysis of the AARP cohort32
, which included prevalent cases of any cancer except pancreatic cancer, as well as deceased pancreatic cancer cases (n = 1,151), reported 1.3-fold increased risk of pancreatic cancer in the highest versus lowest quintile of free fructose intakes (not including fructose from sucrose). Consistent with our findings, they also observed an increased risk for fructose from fruit and fruit juice32
. A similar suggestion came from other cohorts, which showed elevated risk for pancreatic cancer with high intake of free fructose13, 33
and fruit, but not fruit juice13
. Two cohorts, however, found no association between free fructose intake and pancreatic cancer risk34–35
. The evidence for pancreatic cancer risk and other sugars is also inconclusive; the suggestion for an increased risk with total sugar intake found by one cohort13
was not confirmed by others34, 36
; three cohorts found no association with sucrose intake 13, 33–34
, and one found the association with sucrose confined to the first 2 years of follow-up35
. In our analysis, we did not find an association between added sugars
intake and pancreatic cancer risk, as earlier reported by this14
and another cohort13
In our cohort, we could not confirm the finding for a positive association between high sugars intake and risk of colorectal cancer, mainly originating from case control studies2
. Among previous cohorts37–41
, one study showed an increased risk with both sucrose and fructose intake37
, while others found neither sucrose nor fructose to be associated with risk37–38
. None of the cohorts reported a significant association with total sugars intake39–41
A few mechanisms can explain the role of sugars in carcinogenesis and they are likely to be site specific. The synthesis of insulin and IGF-I induced by the glycemic effect of diets high in added sugars
may enhance tumour development through promoting cell proliferation and inhibiting apoptosis, stimulating synthesis of sex steroids3
, or through promoting production of vascular endothelial growth factor (VEGF), which supports tumor growth, and promotes tumor cell migration42
. Another potential mechanism is the increased oxidative stress induced by postprandial hyperglycemia4
. As a potent reducing sugar43
, fructose can produce advanced glycation end-products (AGEs), which may be involved in development and progression of cancers44
. Fructose was also shown to increase serum uric acid, which can lead to insulin resistance and hyperinsulinemia45
. Sugars, to the extent that they contribute to energy intake, may promote obesity, which by favoring insulin resistance and elevated levels of bio-active IGF-I, leptin, sex steroid hormone and pro-inflammatory factors may increase the risk for certain cancers46
. We found no evidence of mediation or interaction effect by BMI for any of the obesity-related cancers suggesting that sugars may act through insulin, the IGF system or other mechanism independent of obesity.
We observed differences in the associations between men and women, which may have been due to behavioral, biological, genetic or hormonal gender differences, or due to the tendency among female respondents to report dietary intake differently than men47
. Similarly to our positive findings, a previous report of the NIH-AARP study on the association of glycemic index (GI) and glycemic load (GL) and cancer risk found GI to be positively associated with esophageal cancer risk in men, and GL to be inversely associated with total cancer risk in men, and with risk of ovarian, liver and pancreatic cancer in women48
Ours is the first cohort to investigate the association between different types of sugars and multiple malignancies. Apart from the evidence on highly prevalent cancers, the available epidemiologic data on sugars in relation to other cancer types have been limited, while our large sample size provided the opportunity to assess effects of sugars on rare cancers. A particular strength of the analysis is that we created cancer specific models pertinent to each cancer site, therefore carefully controlling for potential site-specific risk factors. We were also first to investigate the effect of added sugars, added sucrose and added fructose in relation to various cancers.
The problem of multiple comparisons is inherent to this type of analysis, and there is high probability that some of the findings may have occurred due to a chance. However, this is an exploratory and not a confirmatory analysis, and more detailed investigations with relevant risk factors, histological type, or cancer staging are warranted before any association with sugars intake is confirmed or ruled-out. Even though we adjusted for potential confounders, there is still a possibility of residual confounding, particularly from unknown risk factors in the analysis of under-investigated low-incidence cancers. Furthermore, the lack of reduced risk for lung and oral cancer in our never smokers, which was observed in the main analyses, suggests that the latter may have been due to residual negative confounding from smoking. The measurement error associated with self-reported intake of sugars, which are particularly prone to misreporting49
, possibly affected the magnitude of the observed risk estimates and may have distorted the confidence intervals. Although it may be theoretically possible that the measurement error could have inflated the risk estimates for some of the cancers for which we are seeing significant results, it is much more likely that measurement error attenuated their true risk estimates, which in reality are even stronger; whereas for the cancers with weaker true association with sugars, it may have attenuated the association towards null.
In summary, in our large prospective study, we found no association between dietary sugars measured by an FFQ and risk of colorectal or any other major cancer. The problematic estimation of sugars intake renders the possibility that there still may be some associations to cancer risk that we have not been able to detect using the FFQ. Investigation of the effect of sugars densities in a substitution model vs. the effect of absolute sugars amounts in a partition model generated similar findings. The effects observed on some of the rare cancers, such as pleural, esophageal and small intestinal cancer, as well as on ovarian cancer, are intriguing and open questions on possible mechanisms, but may have been due to a chance, and warrants further investigation.