Inherited Genetic Risk

Colorectal cancer is a major cause of morbidity and mortality throughout the world.1 It accounts for over 9% of all cancer incidence.2,3 It is the third most common cancer worldwide and the fourth most common cause of death.2 It affects men and women almost equally, with just over 1 million new cases recorded in 2002, the most recent year for which international estimates are available.1,4,5,6 Countries with the highest incidence rates include Australia, New Zealand, Canada, the United States, and parts of Europe. The countries with the lowest risk include China, India, and parts of Africa and South America.3

In the United States, colorectal cancer is the third most common cancer diagnosis among men and women (Figs. 1 and ​and22).7,8,9,10,11,12 There are similar incidence rates for cancer of the colon in both sexes, and a slight male predominance for rectal cancer.2,7,8 In 2005, the most recent year for which U.S. statistics are currently available, ~108,100 and 40,800 individuals were diagnosed with cancer of the colon and rectum, respectively.7 For 2008, it was estimated that ~148,900 new cases would be diagnosed and ~49,900 people would die of the disease.10,11,12

Figure 1
Figure 1
Top 10 U.S. cancer sites in 2005: men, all races. From U.S. Cancer Statistics Working Group.7
Figure 2
Figure 2
Top 10 U.S. cancer sites in 2005: women, all races. From U.S. Cancer Statistics Working Group.7
Geographic Variations

Worldwide, colorectal cancer represents 9.4% of all incident cancer in men and 10.1% in women. Colorectal cancer, however, is not uniformly common throughout the world.3 There is a large geographic difference in the global distribution of colorectal cancer. Colorectal cancer is mainly a disease of developed countries with a Western culture.3 In fact, the developed world accounts for over 63% of all cases.8 The incidence rate varies up to 10-fold between countries with the highest rates and those with the lowest rates.1,9 It ranges from more than 40 per 100,000 people in the United States, Australia, New Zealand, and Western Europe to less than 5 per 100,000 in Africa and some parts of Asia.2 However, these incidence rates may be susceptible to ascertainment bias; there may be a high degree of underreporting in developing countries.

Temporal Trends

Different populations worldwide experience different incidence rates of colorectal cancer, and these rates change with time. In parts of Northern and Western Europe, the incidence of colorectal cancer may be stabilizing, and possibly declining gradually in the United States.10 Elsewhere, however, the incidence is increasing rapidly, particularly in countries with a high-income economy that have recently made the transition from a relatively low-income economy, such as Japan, Singapore, and Eastern European countries.2,3,8 Incidence rates have at least doubled in many of these countries since the mid-1970s.4,12,13

In the United States, male and female colorectal cancer incidence rates declined from the mid-1980s to the mid-1990s, followed by a short period of stabilization. From 1998 to 2005 incidence rates have again declined—an average of 2.8% per year for men and 2.2% per year among women.10 These decreases in colorectal cancer incidence have been largely attributed to screening programs that may have improved the detection of precancerous polyps.11 However, although national incidence rates have declined slightly over the last decade, the burden of disease remains high, and disproportionate within demographic subpopulations. For instance, before the 1980s, incidence rates for white men were higher than for black men and approximately equal for black and white women. Since that time, incidence rates have been higher for men than women, and higher among the black population versus the white population.

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Worldwide mortality attributable to colorectal cancer is approximately half that of the incidence. Nearly 530,000 deaths were recorded in 2002, that is, ~8% of all cancer deaths.2,8 It is estimated that 394,000 deaths from colorectal cancer still occur worldwide annually,3 making colorectal cancer the fourth most common cause of death from cancer.2,8 In the United States, colorectal cancer is the second leading cause of death among cancers that affect both men and women.7,8,9,10,11,12,14,15 It was estimated that ~49,960 people from the United States would die of the colorectal cancer in 2008.11,12,16

In North America, New Zealand, Australia, and Western Europe, mortality from colorectal cancer in both men and women has declined significantly.4 However, in some parts of Eastern Europe, mortality has been increasing by 5 to 15% every 5 years.8 In the United States, deaths from colorectal cancer have decreased significantly by 4.3% per year from 2002 to 2005.12 The age-standardized death rate was 18.8 per 100,000 men and women combined per year.17 The current trends in mortality statistics from many of the developed countries are encouraging. However, it is generally difficult to interpret temporal changes in mortality as they are influenced by trends over time in incidence and survival. The incidence rate may be a more appropriate indicator of trends in disease occurrence. Colorectal cancer incidence is unaffected by changes in treatment and survival, although it has been shown to be influenced by improved diagnostic techniques and screening programs.

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Colorectal cancer survival is highly dependent upon stage of disease at diagnosis, and typically ranges from a 90% 5-year survival rate for cancers detected at the localized stage; 70% for regional; to 10% for people diagnosed for distant metastatic cancer.11,17 In general, the earlier the stage at diagnosis, the higher the chance of survival.

Since the 1960s, survival for colorectal cancer at all stages have increased substantially.11 The relative improvement in 5-year survival over this period and survival has been better in countries with high life-expectancy and good access to modern specialized health care. However, enormous disparities in colorectal cancer survival exist globally and even within regions.3,5,18 This variation is not easily explained, but most of the marked global and regional disparity in survival is likely due to differences in access to diagnostic and treatment services.3 In the United States, the 5-year survival for colorectal cancer improved from 1995 to 2000 by more than 10% for both men and women, from 52 to 63% in women and from 50 to 64% in men.11 The increase in survival during this period was not uniform among racial groups, however, and was reduced among non-whites compared with whites.12,17,18

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Several risk factors are associated with the incidence of colorectal cancer. Those that an individual cannot control include age and hereditary factors. In addition, a substantial number of environmental and lifestyle risk factors may play an important role in the development of colorectal cancer; modifiable risks factors will be discussed in the next section.


The likelihood of colorectal cancer diagnosis increases after the age of 40, increases progressively from age 40, rising sharply after age 50.2,17 More than 90% of colorectal cancer cases occur in people aged 50 or older.13,17 The incidence rate is more than 50 times higher in persons aged 60 to 79 years than in those younger than 40 years.17,19 However, colorectal cancer appears to be increasing among younger persons.20,21 In fact, in the United States, colorectal cancer is now one of the 10 most commonly diagnosed cancers among men and women aged 20 to 49 years.14

Tables ​Tables11 and ​and22 show the proportion of men or women in the United States who will be diagnosed with colorectal cancer over different time intervals.17 The time intervals are based on the person’s current age.

Table 1
Table 1
Percentage of U.S. Men Who Develop Colorectal Cancer over 10-, 20- and 30-Year Intervals According to Their Current Age, 2003–2005
Table 2
Table 2
Percentage of U.S. Women Who Develop Colorectal Cancer over 10-, 20- and 30-Year Intervals According to Their Current Age, 2003–2005
Personal History of Adenomatous Polyps

Neoplastic polyps of the colorectum, namely tubular and villous adenomas, are precursor lesions of colorectal cancer.8 The lifetime risk of developing a colorectal adenoma is nearly 19% in the U.S. population.15 Nearly 95% of sporadic colorectal cancers develop from these adenomas.19 An individual with a history of adenomas has an increased risk of developing colorectal cancer, than individuals with no previous history of adenomas.16 A long latency period, estimated at 5 to 10 years, is usually required for the development of malignancy from adenomas.16,22 Detection and removal of an adenoma prior to malignant transformation may reduce the risk of colorectal cancer.23 However, complete removal of adenomatous polyp or localized carcinoma is associated with an increased likelihood of future development of metachronous cancer elsewhere in the colon and rectum.16

Personal History of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a term used to describe two diseases, ulcerative colitis and Crohn disease. Ulcerative colitis causes inflammation of the mucosa of the colon and rectum. Crohn disease causes inflammation of the full thickness of the bowel wall and may involve any part of the digestive tract from the mouth to the anus. These conditions increase an individual’s overall risk of developing colorectal cancer.13 The relative risk of colorectal cancer in patients with inflammatory bowel disease has been estimated between 4- to 20-fold.8 Therefore, regardless of age individuals with IBD are highly encouraged to be screened for colorectal cancer on a more frequent basis.

Family History of Colorectal Cancer or Adenomatous Polyps

The majority of colorectal cancer cases occur in persons without a family history of colorectal cancer or a predisposing illness. Nevertheless, up to 20% of people who develop colorectal cancer have other family members who have been affected by this disease.2,24 People with a history of colorectal cancer or adenomatous polyps in one or more first-degree relatives are at increased risk. It is higher in people with a stronger family history, such as a history of colorectal cancer or adenomatous polyps in any first-degree relative younger than age 60; or a history of colorectal cancer or adenomatous polyps in two or more first-degree relatives at any age.25 The reasons for the increased risk are not clear, but it likely due to inherited genes, shared environmental factors, or some combination of these  Approximately 5 to 10% of colorectal cancers are a consequence of recognized hereditary conditions.18 The most common inherited conditions are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), also called Lynch syndrome. Genes responsible for these forms of inherited colorectal cancer have been identified. HNPCC is associated with mutations in genes involved in the DNA repair pathway, namely the MLH1 and MSH2 genes, which are the responsible mutations in individuals with HNPCC.2,26 FAP is caused by mutations in the tumor suppressor gene APC.9

HNPCC may account for ~2 to 6% of colorectal cancers.2,13 The lifetime risk of colorectal cancer in people with the recognized HNPCC-related mutations may be as high as 70 to 80%,27,28 and the average age at diagnosis in their mid-40s.13 MLH1 and MSH2 mutations are also associated with an increased relative risk of several other cancers, including several extracolonic malignancies, namely cancer of the uterus, stomach, small bowel, pancreas, kidney, and ureter.2 FAP accounts for less than 1% of all colorectal cancer cases.2,13,22 Unlike individuals with HNPCC, who develop only a few adenomas, people with FAP characteristically develop hundreds of polyps, usually at a relatively young age, and one or more of these adenomas typically undergoes malignant transformation as early as age 20.22 By age 40, almost all people with this disorder will have developed cancer if the colon is not removed.2,13 APC-associated polyposis conditions are inherited in an autosomal dominant manner. Approximately 75 to 80% of individuals with APC-associated polyposis conditions have an affected parent. Prenatal testing and preimplantation genetic diagnosis are possible if a disease-causing mutation is identified in an affected family member.29