Etiology
The essential element of the etiology of colorectal cancer is a process of genetic change in the epithelial cells of the colonic mucosa.[ref: 16] These changes are discussed more fully in the Chapter 33.1 that address the molecular biology of this disease. Epidemiologic factors have provided initial evidence about the specific factors that initiate the process of carcinogenesis in the large bowel mucosa.[ref: 17] Chief among the factors that can initiate colorectal cancer development are a predisposition to mutagen effects, fecal mutagens, meat intake, bile acids, altered vitamin and mineral intake, and fecal pH.
Predisposition to Mutagen Effects
There is an interaction between mutagen exposure and genetic constitution. Metabolic pathways may be altered by polymorphisms in genes responsible for detoxifying mutagens. [ref: 18] Protection from the effects of mutagen-induced DNA damage is achieved by a range of detoxification enzymes. Examples are reduced glutathione S-transferase (GSH transferase), DT-diaphorase, and N-acetyltransferase. [ref: 19] Differences among individuals can account for susceptibility to mutagens from the diet. An example is a polymorphism in N- acetyltransferase, an enzyme that catalyzes the formation of mutagenic products from heterocyclic amines, which can play a role in colorectal cancer development.[ref: 20] Heterocyclic amines are substances formed in cooked meats. Differences in N-acetyltransferase activity classify individuals as slow or fast acetylators. Risk for colorectal cancer development increases with the level of red meat consumption in fast acetylators but not in slow acetylators. [ref: 21] Individuals with risk factors for colorectal cancer have significantly lower levels of GSH transferase activity in their blood lymphocytes.[ref: 22] Strategies to enhance the expression of detoxifying enzymes are available. [ref: 23]
Fecal Mutagens
Mutagenic compounds such as fecapentaenes, 3-ketosteroids, and heterocyclic amines in the stool may be produced by the interaction of digestion and food products. [ref: 24] These compounds produce reactive molecules that may form bulky adducts to DNA. One of the chief influences of diet is the production of fecal mutagens by certain diets. Changes in the fecal microflora indicate that changes in diet may alter mutagenic activity by altering extracellular superoxide formation.[ref: 25] For instance, a change in a lactovegetarian diet to a diet with increased fiber intake caused a dilution of mitogenic activity within the stool. [ref: 26] Other factors may moderate the effects of fecal mutagens. Intake of antioxidants reduces the mutagenicity of compounds in the stool. Changes in intestinal transit time owing to fiber intake affects the exposure of the mucosa to mutagens. In addition to mutagenic compounds such as fecapentaenes, the presence of other products of digestion such as 3-ketosteroids, which are products of cholesterol metabolism, may act as tumor promoters or initiators.
Meat Intake
Armstrong and Doll (1975) described the high correlation of meat intake and mortality from colorectal cancer. Among the risk factors are the intake of red meats and the compounds that result from cooking meats at high temperatures. [ref: 27] In a study of meat preparation, it was observed that the association between red meat and colorectal cancer could be due to heterocyclic amines present in cooked meat. [ref: 28] This mechanism has been implicated in the high incidence of colorectal cancer in New Zealand. [ref: 29] The method of red meat preparation and frequency of intake can be correlated with the prevalence of distal colorectal adenomas. Subjects who ate browned, fried red meat more than once per week had an OR of 2.2 for distal colorectal adenomas, as compared with those who ate lightly browned red meat one time or less per week. [ref: 30] In Western countries, fried meat is the main source of exposure to heterocyclic amines. Nurses who consumed the highest ratio of red meat to white meat had a higher relative risk (RR) of colon cancer (OR 2.49, P <.001). [ref: 31]
Bile Acids
Normal bile acids that are related to the digestion of fat can induce intestinal mucosal hyperproliferation, which acts as a marker for neoplasia risk. [ref: 32] The presence of bile acids correlates with fat consumption, which is a known risk factor for colorectal cancer.[ref: 33] Bile acids have been shown to activate AP-1, a transcription factor associated with the promotion of neoplastic transformation in colonic cells. [ref: 34] They are also able to induce apoptosis, and variations in the epithelial apoptotic response to bile acids may correlate with risk. [ref: 35] Cholecystectomy can result in high levels of bile acids in the cecum and ascending colon and appears to increase the frequency of right-sided carcinoma. In a retrospective study of colorectal cancer patients, it was found that levels of the secondary bile acid deoxycholic acid were higher than normal and that the ratio between deoxycholic acid and cholic acid may be an indicator of risk. [ref: 36]