Diet and cancer risk

Following cardiovascular disease, cancer is the second leading cause of death in most affluent countries. It also contributes significantly to mortality rates among adults in developing countries. In the United States, about one in three persons will be diagnosed with cancer during their lifetime and about 60% of those diagnosed will die of cancer. Because rates of cardiovascular death have been declining rapidly and overall cancer mortality has not substantially changed, cancer will likely become the most important cause of death in the United States. Although overall cancer rates among adults vary only modestly around the world, the types of cancers are dramatically different. In most affluent countries, cancers of the lung, colon, breast, and prostate contribute most to incidence and mortality. In poorer regions and the Far East, cancers of the stomach, liver, oral cavity, esophagus, and uterine cervix are most important. However, cancer incidence rates are very dynamic; many areas of the world are experiencing a transition from the cancer incidence patterns of poorer to those of affluent areas. Rates of breast and colon cancer have been increasing in almost all countries.

The dramatic variations in cancer rates around the world and changes over time imply that these malignancies  are potentially avoidable if we were able to identify and then avoid the causal factors. For a few cancers, the primary causes are well known, such as smoking in the case of lung cancer; but for most others, the etiologic factors are less well established. However, strong reasons exist to suspect that dietary and nutritional factors may account for many of these variations in cancer rates. First, a role of diet has been suggested by observations that national rates of specific cancers are strongly correlated with aspects of diet such as per capita consumption of fat.
A multitude of steps in the pathogenesis of cancer have been identified in which dietary factors could plausibly act either to increase or decrease the probability that the clinical cancer will develop. Inadequate intake of dietary factors needed for DNA synthesis, repair, and methylation, such as folic acid, also could influence the risk of mutation or gene expression. The rate of cell division influences whether DNA lesions are replicated and is thus likely to influence the probability of cancer developing. Thus, energy balance and growth rates, which can be influenced by a variety of essential nutrients, could affect cancer rates. Dietary factors can influence endogenous hormone levels, including estrogens and various growth factors, which can influence cell cycling, and thus potentially cancer incidence. Estrogenic substances found in some plant foods also can interact with estrogen receptors, and thus could either mimic or block the effects of endogenous estrogens. Many other aspects of diet can alter cell proliferation or differentiation either by direct hormonal effects, such as by vitamins A or D, or indirectly by influencing inflammatory or irritative processes, such as specific fatty acids that are precursors of prostaglandins or that inhibit their synthesis.

Diet is a complex composite of various nutrients andnonnutritive food constituents, and many types of human cancer exist, each with its own pathogenetic mechanisms. Thus, the combinations of specific dietary factors and cancers are almost limitless.
A positive energy balance during adult life and the resultant accumulation of body fat also contributes significantly to several human cancers. The best-established relationships are with cancers of the colon, kidney, pancreas, esophagus (adenocarcinoma), endometrium, and gall bladder. The relation between body fatness and breast cancer is more complex. Before menopause, women with greater body fat have reduced risk of breast cancer, and after menopause a positive but weak association with adiposity is seen. 

In comparisons among countries, rates of colon cancer are strongly correlated with national per capita disappearance of animal fat and meat. Higher body weight increases risk and higher levels of physical activity reduce risk of colon cancer indicates that at least part of the high rates in affluent countries previously attributed to fat intake may result from sedentary lifestyle and excess energy intakes.

Rates of other cancers that are common in affluent countries, including those of the endometrium and ovary, are, of course, also correlated with fat intake internationally.

Coincident with the strong emphasis on lowering dietary fat over the past several decades, grain consumption in the United States increased 50%. Certain forms of carbohydrate are hypothesized to increase cancer risk, by causing spikes in postprandial blood glucose concentrations and circulating insulin. These carbohydrates with a “high glycemic index” are associated with higher postprandial insulin and higher fasting insulin in insulin-resistant states. According to some studies, a significant increased risk of colorectal cancer was associated with higher glycemic load and index and pancreatic cancer risk was increased by 50% with a high glycemic load. High glycemic load and index diets were associated with an increased risk of endometrial cancer, a cancer strongly associated with obesity and insulin resistance.

Epidemiologic studies have not found a clear association between high protein intake, at least in adulthood, and risk of cancer. In the vast majority of studies, no evidence exists of deleterious effects of some of the major sources of protein, including fish, poultry, and plant sources.

Red meat intake has been linked with risk of several cancers, most notably of the colon, rectum, and prostate. Meat consumption increases 12% to 17%  colon cancer risk with each 100-g increment of red meat intake daily (slightly 3 oz) and a 49% increased risk for each 25-g increment. Higher red meat intake increased 30% risk of prostate cancer.

In the United States, dairy products are the major source of dietary calcium and vitamin D and an important source of protein, saturated fat, and minerals. High milk consumption was associated with a lower risk of colorectal cancer in some studies and higher intakes of milk and total dairy products (but not cheese) were associated with reduced risk of colon but not rectal cancer. Some studies of breast cancer showed decreased risk of breast cancer with higher milk intake. One study showed high-fat dairy products associated with an increased risk of premenopausal breast cancer.

In contrast with potential benefits for colorectal cancer and possibly breast cancer, high intake of dairy products has been associated with an increased risk of prostate cancer.

Fruits and vegetables have received much interest because they contain numerous substances with potential anticarcinogenic activity. Diets high in fruits and vegetables were consistently associated with lower risk of some, but not all, cancers. Some types of fruits and vegetables may have potential deleterious effects. For example, potatoes and some fruit juices have a high glycemic index and increase insulin secretion. In the United States 29% of fruit is consumed as fruit juice, and potatoes and potato products make up 27% of total vegetable consumption, whereas broccoli (0.8%) and dark green vegetables (1%) make up a small amount of total vegetables consumed. From an epidemiologic perspective, some of the promising leads include tomato or lycopene-containing foods and prostate cancer; cruciferous vegetables and several cancer sites including prostate, bladder, and lung cancer; allium vegetables and stomach cancer; folate-rich fruits and vegetables and colon cancer; and citrus fruits and lung cancer.
Fruits and vegetables contain a myriad of biologically active chemicals, including both recognized nutrients and many more nonnutritive constituents, that potentially could play a role in protection against cancer.

High consumption of alcohol, particularly in combination with cigarette smoking, is a well-established cause of cancer of the oral cavity, larynx, esophagus, and liver. One or two drinks per day increase the risk of breast cancer. High intake of alcohol increases risk of colorectal cancer.

Calcium has been proposed to reduce risk of colorectal cancer by binding to toxic secondary bile acids and ionized fatty acids to form insoluble soaps in the lumen of the colon or by directly reducing proliferation,
stimulating differentiation, and inducing apoptosis in the colonic mucosa. Large prospective studies have consistently shown a modest and significant inverse association between calcium intake and colorectal cancer risk. In contrast with colon cancer, higher calcium intake has been associated with an increased risk of total or advanced prostate cancer risk. 

The relation between vitamin D status and cancer risk has been investigated using a number of approaches to estimate vitamin D status, including direct measures of circulating 25(OH) vitamin D concentrations, surrogates, or determinants of 25(OH) vitamin D, including region of residence, intake, and sun exposure estimates. Several lines of evidence strongly support a role for vitamin D in lowering risk for colorectal cancer incidence.

Folate is important for DNA methylation, repair, and synthesis. Epidemiologic studies have linked low folic acid intake with higher risk of several cancers, most notably colorectal, breast, and possibly cervical cancer. Long-term use of folic acid–containing multivitamin supplements is associated with a 20% to 70% reduction in risk of colon cancer. An additional supplement of folic acid is unlikely to be beneficial, and may even be harmful, for those who already have had a colonic neoplasm and have adequate folate intake.

Oxidant byproducts of normal metabolism and smoking cause extensive damage to DNA, protein, and  lipids. DNA repair enzymes efficiently repair damage but antioxidant defenses are imperfect. Antioxidants may reduce the risk of cancer by neutralizing reactive oxygen species or free radicals that can damage DNA. Vitamin C is the major water-soluble antioxidant, and vitamin E is the major lipid-soluble, membrane-localized antioxidant in humans. However, epidemiologic studies have not consistently supported a role for vitamins C and E in cancer risk. Vitamin C can interfere with formation of nitrosamines in the stomach - carcinogens formed endogenously from precursors present in the diet and tobacco smoke. However, chemoprevention trials of stomach cancer in high-risk populations have not conclusively supported a benefit from vitamin C supplements, but several antioxidant nutrients were associated with regression of gastric dysplasia.

Selenium functions through selenoproteins, including selenium-dependent glutathione peroxidases that defend varies depending on the selenium content of soil where plants are grown or animals are raised. Selenium has been strongly associated with reduced prostate cancer risk (a secondary end point) in one trial of selenium supplementation and skin cancer. One study suggested that selenium may be important in inhibiting progression of prostate cancers.