1 INTRODUCTION

Recent estimates from the International Agency for Research on Cancer (IARC) rank bladder cancer globally as the seventh and seventeenth most common malignancy for men and women, respectively.^{1, 2} Most (75%) cancers are nonmuscle-invasive bladder cancer (NMIBC) that frequently recur but require intensive treatment and follow-up measures posing a large burden on national health care budgets and patient quality of life.^{2, 3}

Epidemiological studies have identified several factors which potentially influence bladder cancer risk, including; sex, smoking, age and occupation.^3-5 In addition, evidence suggests that other factors related to environmental and lifestyle (eg, body mass index [BMI], physical activity and diet) also might affect the bladder cancer risk.^{6, 7} Since the bladder is an excretory organ, diet might especially play an essential role in the development of bladder cancer.⁸ Previous research reported that high fluid, fruit, vegetable and yogurt intakes are associated with a reduced risk,⁹ while barbecued meat, pork and total fat intakes are associated with an increased risk.^10-12

Nutritional observational studies have long focused on associations between single food items and disease risk. However, given that individuals do not consume foods (or nutrients) in isolation, but in a complex combination of multiple foods (or nutrients), this single food item approach might be unable to measure the impact of the interaction among different foods on disease risk. Therefore, an increasing number of researchers are taking a more holistic dietary approach, by defining food consumption patterns to characterize a population's dietary intake and to examine potential relationships of these patterns with disease risk. However, although this approach has received much attention during the past few years, evidence on the relation between dietary patterns (DPs) and bladder cancer risk remains scarce. As a consequence of the Neolithic- and Industrial revolutions, which introduced staple foods and new methods of food processing, the Western diet was introduced.¹³ The Western dietary pattern is characterized by high intakes of red and processed meat, fast foods, convenience products, sugary soft drinks, snacks, eggs, refined cereals, high-fat dairy products and hydrogenated fat.^14-17 Particularly meats, eggs and dairy products are considered as prominent features of the Western diet.^18-20 This dietary pattern has been linked to a range of health outcomes, including several types of cancer. Evidence for any association between a Western dietary pattern and bladder cancer risk is limited. To the best of our knowledge, only one study has investigated this association. In a multi-centric, hospital-based, case-control study in Montevideo, Uruguay, it was found that people who adhered to a Westernized diet had 2.35 times higher risk of bladder cancer.²¹

Given the biases to which case-control studies are prone, we aimed to investigate prospectively the potential association between adherence to a Western dietary pattern and the risk of bladder cancer, by pooling data from 13 prospective cohort studies in the BLEND consortium.

2 METHODS

3 RESULTS

4 DISCUSSION

Using prospective cohort studies data from the BLEND consortium, we investigated associations between adherence to a Western dietary pattern and bladder cancer risk and observed an overall direct association between a high adherence to Western dietary pattern and bladder cancer risk for men, but not women. Analyses stratified by disease subtype showed similar results to the overall findings, indicating that the association is unlikely to be confounded by factors that might differ between the different bladder cancer subtypes.

Although we are the first to examine an a priori defined Western dietary pattern in association with bladder cancer risk, a previous study, identified a factor analysis derived Western dietary pattern to be associated with bladder cancer risk.²¹ De-Stephani et al suggested that adherence to a Western dietary pattern is associated with a 2.3-fold risk of bladder cancer. Similar results were reported for bladder cancer recurrence, with individuals who highly adhere to the Western dietary pattern experiencing a 1.48 times higher risk of recurrence compared to those with low adherence to the Western dietary pattern.

Although evidence of association for the whole Western dietary pattern with bladder cancer risk is limited, several studies have focused on some key elements of this dietary pattern and reported positive associations. Red and processed meat is such an element positively associated with bladder cancer risk. A recent meta-analysis showed, by combining results from five cohort studies and eight case-control studies, an increment of 50 g of processed meat per day was associated with 20% increased risk of bladder cancer.⁴⁰ In addition, the authors showed that red meat consumption was associated with bladder cancer, with a 51% increased risk per increment of 100 g per day. However, this association with red meat consumption could only be observed among case-control studies. More recently, this association was confirmed by a cohort study.⁴¹ The effect of meat consumption may be explained by the carcinogenic compounds that are produced during the cooking and processing of meat, which includes nitrate, nitrite, heterocyclic amines and polycyclic aromatic hydrocarbons. Since these compounds are excreted in the urine, they come in close contact with the inner lining of the bladder wall which may exert a carcinogenic effect on urothelial cells.

Another element of the Western dietary pattern that might explain the adverse effect of this diet on bladder cancer risk is fat intake.^{10, 42, 43} A meta-analysis conducted in 2000 by Steinmaus et al,⁴⁴ found that high fat intake significantly elevated the risk of bladder cancer (relative risk [RR] = 1.37, 95% CI: 1.16, 1.62). This was confirmed by the Netherlands Cohort Study on diet and cancer that reported that a high intake of butter increased bladder cancer risk by 61%.⁴⁵ In contrast, a Japanese cohort study could not find an association between butter intake and bladder cancer risk.⁴⁶ In line with these findings, a Belgian case-control study could not detect any association between high intake of animal products, which are also high in their fat content, and bladder cancer risk.⁴⁷ More research on fat consumption, and the different sources of fat, is needed to elucidate any role of fat intake and different sources of fat on bladder cancer risk.

Eggs contain a lot of cholesterol, which has been shown to increase the formation of secondary bile acids in both humans and animals. Bile acids are linked to several mechanisms causing cancer.⁴⁸ In addition, eggs can also be a source of heterocyclic amines when cooked in high temperatures.⁴⁹ A meta-analysis, including four cohort studies and nine case-control studies, however, did not observe an association between egg consumption and bladder cancer risk, except for a possible positive relationship with the intake of fried eggs.⁵⁰ It, therefore, remains inconclusive whether egg intake contributes to the positive association of the Western dietary pattern with bladder cancer risk identified in our study.

Sugar is another important element of the Western dietary pattern that has been investigated but its influence on risk of bladder cancer remains inconclusive. While the NIH-AARP Diet and Health Study showed that sugar is not significantly associated with the risk of bladder cancer,⁵¹ Stefani et al,²¹ showed that sugar intake may increases the risk of bladder cancer by 124%. When studying sweetened beverages, which are considered the main sugar source, results are more in line, in that regular consumption is positively associated with bladder cancer risk.^{52, 53} Unfortunately, due to lack of data, we were unable to include sugar-sweetened beverages in our Western dietary pattern analysis, which might have led to underestimation of our result.

In the present study, the sex-stratified results showed a diversity (P-het = .001) in the association between high adherence to the Western dietary pattern and the risk of bladder cancer for men and women. An explanation for this observation might be genetic variability by sex, which might cause a different effect of similar environmental exposures to the bladder carcinogenesis.^{54, 55} It has been suggested that gender disparity in bladder cancer risk could be explained by sex-specific differences in the metabolism of bladder cancer carcinogens that are influenced by sex hormone.⁵⁶ However, the mechanisms by which Western diet could modulate bladder cancer risk differently in men and women remain to be explored. Furthermore, the limited number of women cases (n = 822) could also affect the outcome of the analyses. Research on the epigenetics of diet and bladder cancer remains in its infancy and need to be explored in detail in future research. Results of the sex and smoking stratified analyses showed no difference between smokers and nonsmokers. Therefore, the effect of residual confounding of smoking on the relation between the Western diet and bladder cancer is suggested to be minor. Finally, to determine the single study effect, sensitivity analyses were performed by removing each individual study in turn from the main analysis. Results showed that the main finding remained robust.

5 CONCLUSIONS

In conclusion, our analysis revealed that higher adherence to a Western dietary pattern is associated with increased risk of bladder cancer, particularly for men. This finding supports the hypothesis that Western dietary pattern may play a role in the etiology of bladder cancer. Further research is necessary to investigate the possible mechanisms for the Western dietary pattern effects on carcinogenesis of bladder cancer and to identify the components of Western dietary pattern that may be predominantly responsible for the observed association with bladder cancer risk.

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.

ETHICS STATEMENT

Each participating study has been approved by the local ethics committee. Informed consent was obtained from all individual participants included in each study.