Adherence to a Western dietary pattern and risk of bladder cancer: A pooled analysis of 13 cohort studies of the Bladder Cancer Epidemiology and Nutritional Determinants international study

Abstract Little is known about the association of diet with risk of bladder cancer. This might be due to the fact that the majority of studies have focused on single food items, rather than dietary patterns, which may better capture any influence of diet on bladder cancer risk. We aimed to investigate the association between a measure of Western dietary pattern and bladder cancer risk. Associations between adherence to a Western dietary pattern and risk of developing bladder cancer were assessed by pooling data from 13 prospective cohort studies in the “BLadder cancer Epidemiology and Nutritional Determinants” (BLEND) study and applying Cox regression analysis. Dietary data from 580 768 study participants, including 3401 incident cases, and 577 367 noncases were analyzed. A direct and significant association was observed between higher adherence to a Western dietary pattern and risk of bladder cancer (hazard ratio (HR) comparing highest with lowest tertile scores: 1.54, 95% confidence interval (CI): 1.37, 1.72; P‐trend = .001). This association was observed for men (HR comparing highest with lowest tertile scores: 1.72; 95% CI: 1.51, 1.96; P‐trend = .001), but not women (P‐het = .001). Results were consistent with HR above 1.00 after stratification on cancer subtypes (nonmuscle‐invasive and muscle‐invasive bladder cancer). We found evidence that adherence to a Western dietary pattern is associated with an increased risk of bladder cancer for men but not women.

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][11][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

What's new?
Does diet affect bladder-cancer risk? Individual foods are rarely eaten in isolation, but little is known about the impact of overall dietary habits. In this large, prospective study, the authors found that greater adherence to a Western dietary pattern was associated with a significantly increased risk of bladder cancer in men. (Surprisingly, the same effect was not seen in women.) Further research is needed to identify the specific food types responsible and their mechanisms of bladder carcinogenesis. However, education to encourage changes in general dietary habits may provide a valuable public-health benefit. 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][15][16][17] Particularly meats, eggs and dairy products are considered as prominent features of the Western diet. [18][19][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.

| Study sample
The study was conducted within the of the BLEND consortium.
BLEND is a large international nutritional consortium, which includes 16 prospective cohort studies from several populations. 22 For the current study, data from 13 cohorts with sufficient collected information on the intake of food items of interest (ie, those required for scoring the chosen Western dietary pattern) were included in the analyses.

| Data collection and coding
Details of BLEND consortium protocols and methodology have been described elsewhere. 22 Briefly, the primary data from all included studies were gathered into an integrated database. Data were checked and the food consumption was converted to grams per day by the use of country-specific food tables and the frequency responses. Each study ascertained incident bladder cancer, defined to include all urinary bladder neoplasms according to the International Classification of Diseases for Oncology (ICD-O-3 code C67) using population-based cancer registries, health insurance records or medical records. 38 Dietary data were obtained using a validated food frequency questionnaires (FFQ), and were recorded using the Eurocode 2 food coding system. 39  and smoking status (current/former/never) and quantity (packs/year), all measured at baseline.

| Western diet score
In the present study, eight food groups were selected to define the Western dietary pattern. This selection was based on prior knowledge [14][15][16][17][18][19][20] and data availability and included eggs, butter, margarine, animal fat, sugar and sugar added products, red and processed meats, dressings, and dips. For each food item, a score from 1 to 5 was assigned based on quintiles of overall intake. A score of "1" was assigned to those in the lowest quintiles and "5" was assigned to those in the highest quintiles. Each participant's overall score was calculated by summing the scores received for each individual food item. Accordingly, the score ranged from 8 (minimal adherence) to 40 (highest adherence). Participants were then classified into tertiles (low, medium and high adherence to a Western dietary pattern) according to their score.

| Statistical analysis
Baseline characteristics of study participants were compared between the tertiles of adherence to the Western dietary pattern using analysis of variance or independent sample t test, for continuous variables or ANCOVA for categorical variables. We used the Cox proportional hazard modeling approach with recruitment as the starting point on the time scale to assess the association between adherence to the Western dietary pattern and bladder cancer risk.
Hazard ratios and 95% confidence intervals (CIs) for developing bladder cancer were calculated with the first tertile assigned as a reference group. The proportional hazards assumption was examined graphically and we found no apparent violation of the assumption.
Survival time was estimated by subtracting age at exit by age at entry in the cohort as T0, thereby correcting for age in the analysis.
Study was included as a random effect. The Cox regression models were performed as crude, and adjusted Model 1 for: total energy intake in kilocalories, sex, smoking status (never, former or current smoker) and smoking intensity ([pack/day] * years), and additionally for fluid, vegetables and fruits intake (Model 2). Analyses were stratified on smoking status, sex and disease subtype (nonmuscle-invasive or muscle-invasive disease). All statistical analyses were performed using Stata/SE version 14.2. P values less than .05 were considered as statistically significant.

| 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  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. 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 proportion of bladder cancer cases can be attributed to these factors. 5,59, 60 We were also not able to take into account any possible changes to dietary and lifestyle habits over time, which would better reflect the effect of long-term diet. Likewise, information bias, which as a consequence of self-reported information on food consumption is a common bias in nutritional epidemiology studies, 61 should be taken into account when intenerating results. However, it is expected that the distribution of this bias was not significantly different between cases and noncases, suggesting that the impact of information bias on our findings might be minimal.

| 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.