Uncovering the links between diet and the incidence of bowel cancer

Keywords::

• colorectal cancer
• foods
• incidence
• nutrients
• vitamin D

The International Agency for Research on Cancer (IARC) estimated that approximately 1,200,000 new cases of colorectal cancer (CRC) were diagnosed in 2008 (9.8% of all new cancer cases) making CRC the fourth most common cancer worldwide [1]. Large variations in incidence rates were observed with the lowest incidence rates to be observed in regions of central Africa and south-central Asia and the highest to be observed in western regions of Europe, North America and Australia/New Zealand [1,2]. Although CRC is mainly a disease of high-income countries, there has been a rapid increase in rates of countries that have recently made the transition from a relatively low-income economy, such as Japan, Singapore and eastern European countries. This is also reflected by the fact that the percentage of the new CRC cases recorded in the more developed regions dropped from 65% in 2002 to 59% in 2008 [1].

Dietary risk factors

According to the Food, Nutrition, Physical Activity and the Prevention of Colorectal Cancer update report of the American Institute for Cancer Research/World Cancer Research Fund (AICR/WCRF), which was released in 2011, diet has a very important role in the prevention and causation of CRC [3]. It has also been thought that the role of diet in colorectal carcinogenesis is particularly important when a poor diet is combined with a generally unhealthy lifestyle, consisting of excess calorie intake and weight gain, physical inactivity and high consumption of alcohol [4]. The role of several dietary types, foods or nutrients in colorectal carcinogenesis has been investigated in many observational studies; however the evidence regarding the effect of particular dietary factors is still generally inconsistent.

The most widely studied foods and nutrients in relation to colorectal cancer are folate (4277 hits in a Medline search limited to human studies), dietary fiber (1777 hits), calcium (1570 hits), fruit and vegetables (1083 hits), vitamin D (612 hits) and red and processed meat (387 hits). Below, I will give a brief overview of the current evidence for the most convincing or promising dietary factors as well as for some novel dietary factors that have just recently linked to CRC.

Dietary fiber

The first observation that high fiber intake may decrease colorectal cancer risk was published in 1969 [5] and since then many observational studies, reviews and meta-analyses investigating the role of fiber on CRC development have been published. A meta-analysis including 25 cohort studies revealed a 10% decreased risk per 10 g/day of fiber intake [3], results that strengthened the evidence for the role of high dietary fiber intake in CRC prevention. A similar finding was reported by the most recent analysis of the European Prospective Investigation into Cancer and Nutrition study that included 4517 CRC cases and showed a 13% decrease in CRC risk per 10 g/day increase in fiber [6].

Red & processed meat

Evidence regarding the positive association between CRC and intake of red and processed meat is quite consistent and convincing. In the second report of AICR/WCRF, a systematic review and meta-analysis of observational analytical studies of risks associated with intake of red meat and processed meat showed a positive association with CRC [7]. Regarding red meat, 16 cohort and 71 case–control studies were included with nearly all of them showing a positive association with CRC. A meta-analysis of the cohort data showed that every 50 g/day increase of red meat intake was associated with a 15% increase in CRC risk. Fourteen cohort and 44 case–control studies investigating the association with processed meat were included in this report and meta-analysis of the cohort studies showed a positive association with colorectal cancer risk [7]. A recent systematic review and updated meta-analysis of all prospective studies conducted from 1966 to March 2011 also reported that the risk of colorectal cancer increased by 29% for every 100 g/day of red meat and 21% for every 50 g/day of processed meat intake [8].

Folate (folic acid)

Folate is a water-soluble vitamin that occurs naturally in foods. The role of folate in preventing neural tube defects (NTDs) is well established and a mandatory folic acid fortification in the USA and Canada has led to a 46% reduction of NTDs [9]. There is limited evidence that folate is inversely associated with CRC, and due to the inconsistency of the results of the different observational studies, residual confounding from other nutrients (e.g., fiber) cannot be ruled out [3]. Similarly, a recent meta-analysis of randomized controlled trials (RCTs) assessing the effectiveness of folic acid in preventing colorectal adenomas recurrence or the incidence of colorectal cancer, reported that there is no evidence that folic acid can act as CRC chemo-preventer [10]. Finally, a recent temporal study reported a statistically significant increase in CRC absolute rates both in the USA and Canada for the period that followed the full folic-acid fortification [11].

Vitamin D

Vitamin D has been considered relevant to skeletal disease and calcium metabolism, but there is growing evidence that vitamin D deficiency might be a risk factor for cancer, cardiovascular, metabolic, infectious and autoimmune diseases [12]. Vitamin D has been first linked to CRC through ecological studies revealing that colon cancer mortality rates were highest in places where populations were exposed to the least amounts of natural light [13]. Since then many observational studies have showed that high vitamin D intake or high plasma levels of 25-hydroxyvitamin D (25-OHD) are linked to a decrease in CRC risk [14]. However, the WCRF/AICR report concluded that the evidence suggesting that vitamin D is protective against CRC is limited. A number of large vitamin D RCTs on chronic diseases including cancer (e.g., Vitamin D and Longevity [VIDAL] Trial [UK], Vitamin D and Omega-3 Trial [USA], Finnish Vitamin D Trial [Finland]) are now underway and data from these trials will provide more insight into the protective effect of vitamin D.

Recent dietary factors

Some recent dietary factors that have been proposed to be linked to CRC but have not yet evaluated fully included flavonoids, omega 3 (n-3) fatty acids and high energy snack foods and drinks [15–17]. Flavonoids are biologically active polyphenolic compounds that are widely distributed in a variety of plants [16]. The epidemiologic evidence on flavonoid intake and CRC risk is limited and inconsistent with positive, inverse and null associations to have been reported and it is therefore premature to draw any certain conclusion about their role in colorectal carcinogenesis [18]. All fats consist of fatty acids (organic [carboxylic] acids), which are classified as either saturated or unsaturated, depending on their chemical structure. The role of n-3 fatty acids on the primary prevention of CRC has gained considerable interest in recent years; a few observational studies have assessed their relationship with CRC [17]. However, a recent meta-analysis of seven prospective studies including a total of 489,000 individuals reported insufficient evidence of a protective effect of n-3 fatty acids on CRC risk [19]. Finally, we have very recently identified ‘high-energy snack foods’ and high-energy drinks (including sugar-sweetened beverages and fruit juices) as risk factors for CRC. These positive associations have not been reported previously and merit further investigation as such snacks and beverages are important contributors in European and North American diets [15].

Gene–diet interactions

Polymorphisms in low-penetrance genes may modify the risk of dietary factors. A number of gene–diet interactions in CRC have been suggested including interactions with intakes of meat (NAT1, NAT2, ABCB1, NFKB1), cruciferous vegetables (GSTM1, GSTT1), fiber (CCND1), vitamin D (VDR) and calcium (VDR) [20]. The assessment of such gene–diet interactions may be utilized for identification of biological pathways, but the findings need to be replicated in large preferably prospective studies before definite conclusions can be drawn.

Limitations of dietary association studies

Establishing causal relationships between dietary factors and common diseases using conventional methods can be problematic due to unresolved confounding, reverse causation and selection bias. In a recent review of diet and nutrient factors in relation to colorectal cancer risk, Vargas and Thompson summarized the main limitations of dietary association studies [21]. Some of the main limitations included that the food and nutrient estimations were derived from self-reporting questionnaires, the size effects were generally small and the participants were biased toward being healthy.

Sophisticated statistical and machine learning methods that allow the investigation of causality in observational studies and that can overcome the limitations of conventional epidemiological methods have been applied to investigate the causal effects of nutrients on CRC [12,14]. These methods, though very promising, have proven to need very large sample sizes. One other possible though expensive solution to these limitations will be to conduct single nutrient-based RCT for those nutrients that the observational evidence is promising and may have potentially large public health importance should associations prove to be causal (e.g., vitamin D supplementation for CRC prevention and/or treatment).

Nutritional epidemiology is a challenging field with a number of limitations resulting in inconsistencies in the published literature. A wide range of nutrients or foods have been suggested to be linked to CRC and although the evidence has been promising they failed to replicate in future studies. Therefore, the results of dietary association studies should be interpreted with caution and this needs to always be highlighted especially since scientific reports on diet and cancer are prone to yield wide media attention.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

No writing assistance was utilized in the production of this manuscript.