Final Report Summary - OGAPEF (Obesity and gastrointestinal adenocarcinomas: the independent and joint roles of dietary phytoestrogens and fibres)
Background
Incidence patterns of cancers in the gastrointestinal (GI) tract are intriguing. The abrupt increase and extreme male predominance of oesophageal adenocarcinoma, the continuously decreasing trend of stomach cancer, the inexplicable rarity of small intestinal cancer, and the prevalent occurrence of colorectal cancer indicate distinctly underlying mechanisms regardless of the internally connected GI tract. Contrary to more than two-thirds of the length of the digestive tract and more than 90% of its mucosal surface area, cancer in the small intestine is extremely rare. It accounts for less than 5% of total GI cancers. Few studies have examined the causality of cancer in the small intestine because of limited sample size.
Diet and related nutrients have been postulated to play a role on small intestinal cancer due to the functionality of small intestine in nutrients consumption and absorption. Recent in vitro and animal studies have demonstrated that two phytochemicals, dietary fibre and polyphenols (including phytoestrogens isoflavonoids and lignans) are possibly against gastrointestinal cancer. Polyphenol generally exist in fibre-rich foods. Fibre binds up to 80 percent of polyphenols in fruit and vegetables, which may protect the polyphenols from early digestion in the stomach and small intestine. Whether dietary fibre and polyphenols play an independent and/or joint role on the risk of small intestinal cancer is poorly understood.
Methods
The study was based on the European Prospective Investigation into Cancer and Nutrition (EPIC). Moreover, we initiated an international pooling project (supported by NCI Cohort Consortium) on small intestinal cancer to comprehensively investigate the potential risk factors including diet and nutrients. Data of dietary fibre was retrieved from the EPIC Nutrient Data Base (ENDB); in which the nutritional composition of foods across the different countries has been standardised. Dietary polyphenols were assessed using the Phenol-Explorer database which provided data on 501 polyphenol compounds in 452 plant-based foods. Dietary polyphenols are a large family of related organic plant molecules and are the most abundant dietary antioxidants present in: fruits, vegetables, tea, coffee, herbs and spices. Plant polyphenols can be classified into several groups dependent on the number of phenol rings in their structure. The largest class is flavonoids sub-divided into: flavonols, flavones, isoflavonoids, flavanones, anthocyanidins, and flavanols. Other major polyphenol classes are the stilbenes (resveratrol), phenolic acids (including hydroxybenzoic acids and hydroxycinnamic acids), and the lignans.
Total polyphenol content was calculated as the sum of the contents of individual compounds expressed in mg/100g food fresh weight. All animal foods that contain no or only traces of polyphenols were excluded. Incident cancer cases of small intestine were identified in EPIC by follow-up from 1991 to 2012 based on population cancer registries (Denmark, Italy, Netherlands, Spain, United Kingdom) and other methods such as health insurance records, pathology registries and active contact of study subjects or next of kin (France, Germany, Greece). Cox proportional hazards regression model was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CI) with adjustment for potential confounders. Interaction and effect modification of phytochemicals with body mass index (BMI) and smoking status were further investigated.
Results
In EPIC, we identified 169 small intestinal cancer cases during an average of 13.9 years of follow-up. The overall results did not find an association between polyphenols, including phytoestrogens isoflavonoids and lignans, or dietary fibres and risk of small intestinal cancer. No association was observed for the joint role of dietary fibres and polyphenols on the risk of small intestinal cancer as well. Obesity did not interact with dietary polyphenols or/and fibres on risk of small intestinal cancer, although obesity, especially abdominal obesity seems to be marginally associated with increased risk of small intestinal cancer. The obesity association was apparent in adenocarcinoma of the small intestine. Together with projects implemented in EPIC, significantly negative associations of dietary fibres were observed in other cancer in the gastrointestinal tract, e.g head and neck cancer, oesophageal squamous cell carcinoma, stomach cancer and colon cancer. Dietary polyphenols, e.g. flavanols, flavanones, lignans, stilbenes or hydroxycinnamic acid were associated with decreased risk of head and neck cancer, oesophageal squamous cell carcinoma or stomach cancer. Smoking rather obesity is a strong effect modifier for squamous cell carcinoma in the upper GI tract. In ever smokers, dietary fibres and polyphenols are associated with a consistently reduced risk of squamous cell carcinoma in the oesophagus and head and neck, while in non-smokers this association disappeared.
For the international pooling project on small intestinal cancer, 16 cohorts from 13 countries are participating in the project. In total 1051 cases and 10475 controls have been included in the study. The current results so far showed that obesity, especially abdominal obesity might be associated with risk of small intestinal cancer. We did not find apparent association between dietary factors, e.g. fibres and risk of small intestinal cancer. Further analyses are undertaking and more results would be showed during the coming months.
Conclusion
Based on the EPIC cohort, the study showed that aetiology of small intestinal cancer is largely different from other cancers in the gastrointestinal tract. The current established risk factors for other GI cancers, e.g. obesity and gastroesophageal reflux for oesophageal adenocarcinoma, smoking for squamous cell carcinoma in upper GI tract, and dietary factors (e.g. fibre, red meat) for colorectal cancer might not be the causes of small intestinal cancer. As small intestinal cancer is such a rare malignancy considering its large surface area and absolute length, it aetiology could be something else, e.g. the relatively bacteria-free environment in the small intestine, the active metabolism in the epithelial cell and the metabolites formed in the small intestine. Further studies have been planned to deepen these hypotheses.
Socio-economic impact
The current study provided a comprehensive comparison of risk factors of small intestinal cancer with other cancers in the gastrointestinal tract. Specifically, the current study analysed the potential joint role of fibres and polyphenols, two important phytochemicals, interacting with obesity and smoking on the risk of small intestinal cancer. Although, no association was found in the cancer of the small intestine, the potentially protective effects of dietary fibre and polyphenols on other GI cancer in ever smokers may indicate a potentially intervention strategies on this high cancer risk population.
The added-value and positive impact of the project on the European Union.
This is the first study provided a comprehensive analysis of the joint role of dietary fibres and polyphenols on risk of small intestinal cancer. Furthermore, the international pooling project, the largest study so far on investigating of causality of small intestinal cancer, would provide a full description of risk factors of small intestinal cancer. The findings from the project indicated that: 1) the causality of small intestinal cancer is different from other gastrointestinal cancers; 2) the value of dietary fibre and polyphenols on prevention and treatment of small intestinal cancer is unclear, while the potential association with other gastrointestinal cancers especially in ever smokers might be promising and warranted for further tentative trials.
Incidence patterns of cancers in the gastrointestinal (GI) tract are intriguing. The abrupt increase and extreme male predominance of oesophageal adenocarcinoma, the continuously decreasing trend of stomach cancer, the inexplicable rarity of small intestinal cancer, and the prevalent occurrence of colorectal cancer indicate distinctly underlying mechanisms regardless of the internally connected GI tract. Contrary to more than two-thirds of the length of the digestive tract and more than 90% of its mucosal surface area, cancer in the small intestine is extremely rare. It accounts for less than 5% of total GI cancers. Few studies have examined the causality of cancer in the small intestine because of limited sample size.
Diet and related nutrients have been postulated to play a role on small intestinal cancer due to the functionality of small intestine in nutrients consumption and absorption. Recent in vitro and animal studies have demonstrated that two phytochemicals, dietary fibre and polyphenols (including phytoestrogens isoflavonoids and lignans) are possibly against gastrointestinal cancer. Polyphenol generally exist in fibre-rich foods. Fibre binds up to 80 percent of polyphenols in fruit and vegetables, which may protect the polyphenols from early digestion in the stomach and small intestine. Whether dietary fibre and polyphenols play an independent and/or joint role on the risk of small intestinal cancer is poorly understood.
Methods
The study was based on the European Prospective Investigation into Cancer and Nutrition (EPIC). Moreover, we initiated an international pooling project (supported by NCI Cohort Consortium) on small intestinal cancer to comprehensively investigate the potential risk factors including diet and nutrients. Data of dietary fibre was retrieved from the EPIC Nutrient Data Base (ENDB); in which the nutritional composition of foods across the different countries has been standardised. Dietary polyphenols were assessed using the Phenol-Explorer database which provided data on 501 polyphenol compounds in 452 plant-based foods. Dietary polyphenols are a large family of related organic plant molecules and are the most abundant dietary antioxidants present in: fruits, vegetables, tea, coffee, herbs and spices. Plant polyphenols can be classified into several groups dependent on the number of phenol rings in their structure. The largest class is flavonoids sub-divided into: flavonols, flavones, isoflavonoids, flavanones, anthocyanidins, and flavanols. Other major polyphenol classes are the stilbenes (resveratrol), phenolic acids (including hydroxybenzoic acids and hydroxycinnamic acids), and the lignans.
Total polyphenol content was calculated as the sum of the contents of individual compounds expressed in mg/100g food fresh weight. All animal foods that contain no or only traces of polyphenols were excluded. Incident cancer cases of small intestine were identified in EPIC by follow-up from 1991 to 2012 based on population cancer registries (Denmark, Italy, Netherlands, Spain, United Kingdom) and other methods such as health insurance records, pathology registries and active contact of study subjects or next of kin (France, Germany, Greece). Cox proportional hazards regression model was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CI) with adjustment for potential confounders. Interaction and effect modification of phytochemicals with body mass index (BMI) and smoking status were further investigated.
Results
In EPIC, we identified 169 small intestinal cancer cases during an average of 13.9 years of follow-up. The overall results did not find an association between polyphenols, including phytoestrogens isoflavonoids and lignans, or dietary fibres and risk of small intestinal cancer. No association was observed for the joint role of dietary fibres and polyphenols on the risk of small intestinal cancer as well. Obesity did not interact with dietary polyphenols or/and fibres on risk of small intestinal cancer, although obesity, especially abdominal obesity seems to be marginally associated with increased risk of small intestinal cancer. The obesity association was apparent in adenocarcinoma of the small intestine. Together with projects implemented in EPIC, significantly negative associations of dietary fibres were observed in other cancer in the gastrointestinal tract, e.g head and neck cancer, oesophageal squamous cell carcinoma, stomach cancer and colon cancer. Dietary polyphenols, e.g. flavanols, flavanones, lignans, stilbenes or hydroxycinnamic acid were associated with decreased risk of head and neck cancer, oesophageal squamous cell carcinoma or stomach cancer. Smoking rather obesity is a strong effect modifier for squamous cell carcinoma in the upper GI tract. In ever smokers, dietary fibres and polyphenols are associated with a consistently reduced risk of squamous cell carcinoma in the oesophagus and head and neck, while in non-smokers this association disappeared.
For the international pooling project on small intestinal cancer, 16 cohorts from 13 countries are participating in the project. In total 1051 cases and 10475 controls have been included in the study. The current results so far showed that obesity, especially abdominal obesity might be associated with risk of small intestinal cancer. We did not find apparent association between dietary factors, e.g. fibres and risk of small intestinal cancer. Further analyses are undertaking and more results would be showed during the coming months.
Conclusion
Based on the EPIC cohort, the study showed that aetiology of small intestinal cancer is largely different from other cancers in the gastrointestinal tract. The current established risk factors for other GI cancers, e.g. obesity and gastroesophageal reflux for oesophageal adenocarcinoma, smoking for squamous cell carcinoma in upper GI tract, and dietary factors (e.g. fibre, red meat) for colorectal cancer might not be the causes of small intestinal cancer. As small intestinal cancer is such a rare malignancy considering its large surface area and absolute length, it aetiology could be something else, e.g. the relatively bacteria-free environment in the small intestine, the active metabolism in the epithelial cell and the metabolites formed in the small intestine. Further studies have been planned to deepen these hypotheses.
Socio-economic impact
The current study provided a comprehensive comparison of risk factors of small intestinal cancer with other cancers in the gastrointestinal tract. Specifically, the current study analysed the potential joint role of fibres and polyphenols, two important phytochemicals, interacting with obesity and smoking on the risk of small intestinal cancer. Although, no association was found in the cancer of the small intestine, the potentially protective effects of dietary fibre and polyphenols on other GI cancer in ever smokers may indicate a potentially intervention strategies on this high cancer risk population.
The added-value and positive impact of the project on the European Union.
This is the first study provided a comprehensive analysis of the joint role of dietary fibres and polyphenols on risk of small intestinal cancer. Furthermore, the international pooling project, the largest study so far on investigating of causality of small intestinal cancer, would provide a full description of risk factors of small intestinal cancer. The findings from the project indicated that: 1) the causality of small intestinal cancer is different from other gastrointestinal cancers; 2) the value of dietary fibre and polyphenols on prevention and treatment of small intestinal cancer is unclear, while the potential association with other gastrointestinal cancers especially in ever smokers might be promising and warranted for further tentative trials.