Colorectal carcinoma is the third most commonly diagnosed cancer worldwide. There were 1.2 million newly diagnosed cases and 608,000 cancer-related deaths in 2008, making it the fourth most common cause of death from cancer.¹,² Approximately 60% of colorectal cancers are diagnosed in economically developed regions: The highest estimated incidence rates are observed in Australia, New Zealand, and Western Europe. There is less regional variability with respect to colorectal cancer mortality rates. Both incidence and mortality rates are slightly lower in women than in men (Figure 2.1).

Approximately 143,460 individuals (73,420 men and 70,040 women) in the United States have been diagnosed with colorectal cancer, and 51,690 people have died of this malignancy in 2012.³ The age-adjusted incidence rate is an estimated 46.3 per 100,000 individuals per year, and the age-adjusted annual mortality rate is 16.7 per 100,000. These values are based on 2005 to 2009 data from the Surveillance, Epidemiology and End Results (SEER) Program, National Cancer Institute, U.S. National Institutes of Health (http://seer.cancer.gov), and are based upon findings obtained from specific geographic areas representing 28% of the population.³ Although incidence rates for colon cancer are similar for men and women, rectal cancers occur more often in men.⁴ Recent declines in colorectal cancer incidence in the United States (2.5% annually from 1998 to 2009) reflect the introduction of colonoscopy as a screening tool in the early 1990s and its widespread use beginning in 2001, which coincided with expanded insurance reimbursement.³,⁵

Five-year survival rates for colorectal cancer range from 90% for localized cancers to 12% for individuals with metastatic disease.³,⁶ Stage-independent disparities in survival among regions in the United States and worldwide exist due to differences in access to diagnostic services and treatment. Five-year survival rates have improved significantly over the last few decades in the United States, but death rates continue to be higher among blacks than whites and other racial/ethnic groups (Table 2.1). This disparity in survival has widened in comparison to trends for other cancers.³,⁶

Some colorectal cancer risk factors, such as age, history of polyps, and genetic risk, cannot be altered or modified by the individual. Increasing age is strongly associated with increased colorectal cancer incidence: The median age at colorectal cancer diagnosis in the United States is 69 years, and nearly two-thirds of tumors are diagnosed in persons 65 years of age and older, while only 5% are diagnosed before the age of 45 years.³ Colorectal adenomas are precursor lesions of colorectal cancer.⁷ The lifetime risk of developing a colorectal adenoma may be over 18% in the United States, but detection and removal of polyps before malignant transformation reduces the risk of death from colorectal cancer.⁸,⁹ Although hyperplastic polyps have been considered to have little potential for progression to cancer, large nondysplastic serrated polyps (>1 cm) of the abdominal colon are associated with an increased risk of colon cancer, especially if they are multiple, as discussed in Chapters 4,11, and 12.¹⁰

Only 5% to 6% of colorectal cancers develop in association with heritable disease.¹¹,¹² The most common of these inherited disorders are familial adenomatous polyposis, which results from APC mutations, and Lynch syndrome, which is caused by mutations in DNA repair genes, as discussed in Chapters 11 and 12. Individuals with familial adenomatous polyposis typically develop hundreds of polyps at a young age, and virtually 100% will develop colorectal cancer unless a prophylactic colectomy is performed.¹³ The lifetime risk of colorectal cancer among patients with Lynch syndrome may be as high as 70% to 80%, but cancers are usually diagnosed in the fifth decade of life, which is later than those associated with familial adenomatous polyposis.⁴,¹²

Approximately 20% to 25% of colorectal cancers occur in patients with a family history of colorectal cancer, unassociated with familial adenomatous polyposis or Lynch syndrome. Such tumors are considered familial cancers and are likely due to inheritance of relatively common, low-penetrance genetic variants that portend low to modest cancer risk.¹¹ It is unclear whether familial colorectal carcinomas occur due to an inherited predisposition, shared environmental exposure, or a combination of both. Low-penetrance variants affecting APC, BLM, HRAS1, and TGFβR1 have been described, and recent efforts to uncover additional genetic susceptibility variants have revealed a number of genome-wide associations.¹¹ Genetic variants present in the SMAD7 gene and regions on chromosomes 8q24 and 18q21, all of which are commonly altered in colorectal cancers, have been identified in many people. These variants are associated with a modest (10% to 30%) increased risk in carriers compared with individuals without the variant.¹⁴, ¹⁵ and ¹⁶˜ Other genetic variants in candidate genes interact with diet and lifestyle factors, such as inflammation or insulin-related pathway, and are associated with very modest effects on colorectal
cancer risk. A detailed discussion of the extensive catalog of candidate genetic variants is beyond the scope of this chapter.

Environmental lifestyle and dietary influences are considered to represent modifiable risk factors for colorectal cancer. Epidemiologic studies evaluating associations between the environment and colorectal cancer have shown that colorectal cancer incidence in populations migrating from low-risk to high-risk countries approaches that of the new host nation within a generation or two.¹⁷,¹⁸ For example, offspring of Japanese migrants to the United States have a similar colorectal cancer risk to white Americans that is three to four times that of Japanese people in Japan.¹⁸ Colorectal cancer risk is clearly related to a variety of environmental influences, including medications, exposure to cigarette smoke, physical activity, obesity, and alcohol use. Numerous dietary factors have been implicated in colorectal carcinogenesis, although the evidence is generally more inconsistent than that of lifestyle factors. Methods used to measure dietary influences vary widely and include diet records, diet histories and food frequency questionnaires, 24-hour dietary recall, and other forms of self-reporting. Thus, intake is often misreported or imprecise. Only widely studied dietary factors related to colorectal cancer, such as folate and other B vitamins, fiber from grains, fruits and vegetables, calcium and vitamin D, and red and processed meats, are discussed in this chapter.