Cigarette smoking and colorectal cancer: From epidemiology to bench

Colorectal cancer is the third most commonly diagnosed malignancy in the world. The risk factors include inherited genetic mutations and environmental elements such as a high-fat diet, low-fiber diet and sedentary lifestyle. Cigarette smoking is a serious worldwide health problem and the leading cause of preventable death. Although smoking increases the risk of cardiovascular disease and various cancers such as lung, oral and some gastrointestinal cancers, smoking is currently not recognized as a risk factor of colorectal cancer by either the International Agency for Research on Cancer (IARC) or the US Surgeon General. Accumulating epidemiological studies indicate that cigarette smoking is positively correlated to colorectal adenomatous polyps, and positive associations between cigarette smoking and colorectal cancer risk have been reported. Long-term cigarette smoking increases the risk of colorectal cancer mortality and the likelihood of a mutation occurring in the adenomatous polyposis coli (APC) tumor suppressor gene, which has a "gatekeeper" function in the colonic mucosa. Heavy smoking is associated with an increased risk of obtaining a mutation in BRAF, but not KRAS. Current and long-term smokers are at elevated risk of microsatellite instability high (MSI-H) colorectal cancers and an estimated one in five MSI-H colorectal cancers is attributable to cigarette smoking. Nicotine and its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are two of the most causal elements for smoking-related cancers. Nicotine and NNK have been shown to induce colon cancer growth and even enhance the migration of colon cancer cells, which is a major cause of cancer death. In conclusion, cigarette smoking should be considered a risk factor of colorectal cancer.