proximal tumors in women.

There are great disparities in CRC incidence and mortality between ethnic and racial groups. Both are

highest for African Americans and lowest for Asians/Pacific Islanders, but the differences in mortality

are proportionally larger compared to the differences in incidence. The decline in mortality for CRC that

began in the 1980s did not start affecting African Americans until the 1990s. These differences are

attributed to disparities in access to screening and care. The decline in CRC-related mortality among

African Americans has also accelerated in recent years.2

CRC is the third most common cancer in men and the second most common cancer in women

worldwide, with an estimated 1.4 million new cases diagnosed in 2012 (Fig. 68-2). It is responsible for

8% of cancer deaths worldwide. The age-standardized incidence of CRC varies significantly in different

countries. It is highest in North America, New Zealand, Australia and Western Europe and lowest in

India and many African countries. While the incidence is decreasing in some developed countries

(United States) and stabilizing in others (France, Australia), it is increasing in Asia (Japan) and the

Middle East (Kuwait), Eastern European countries (Czech Republic, Slovakia, Slovenia), and some

Southern European countries (Spain). The increase in incidence has been attributed to changes in risk

factors, such as the Westernization of diets, obesity, and smoking. However, despite the increase in

incidence, mortality for CRC is decreasing in many countries, most likely because of improvements in

both screening and treatment.2

RISK FACTORS

There are numerous factors associated with the risk of CRC (Table 68-1).3 Some are behavioral, and

potentially modifiable. Others are genetic or hereditary, and therefore nonmodifiable. Information

about individual risk factors can be used to reduce incidence and mortality through behavior

modification and screening programs.4 Except for the relatively uncommon hereditary syndromes with

known patterns of inheritance, the relative contribution of inherited and environmental factors to the

development of CRC is controversial. Analysis of cohorts of twins from Scandinavian countries suggests

a significant but relatively minor contribution of hereditary factors to the development of sporadic CRC;

the environment seems to play a larger role in the development of sporadic cancers.5

Figure 68-1. Trends in Colorectal Cancer Incidence and Death Rates by Sex, USA, 1930–2010. (From The American Cancer Society,

Colorectal Cancer Facts and Figures 2014–2016.)

The list of behavioral or modifiable factors includes obesity, physical inactivity, smoking, diet, and

alcohol intake.6 Obesity is associated with increased risk of developing CRC in both men and women.7,8

Abdominal obesity, measured as waist size, seems to be more important than excess weight, particularly

in men. Being overweight increases the risk of CRC, independent of the level of physical activity. The

most physically active people have a 25% lower risk of developing CRC, compared to the least active

people. Both recreational and occupational physical activity reduces CRC risk, and sedentary people

who become physically active later in life do reduce their CRC risk.9 The geographical differences in the

incidence of CRC, and the change in incidence in migrant populations, suggest that diet is probably an

important risk factor.10 The risk of CRC has been associated with a high consumption of red or

processed meats.11,12 On the other hand, the risk of CRC is inversely correlated with the intake of fiber

and whole grains, fruits and vegetable, dairy products and calcium, vitamin D, and folates.6 Alcohol

1761

consumption is causally associated with the development of CRC, and the effect seems to be dosedependent. The risk seems to be higher for men than for women. There is no difference in the effect

with regard to the type of alcohol.13 Smoking increases the incidence and mortality from CRC, and in

particular, rectal cancer.14,15

Table 68-1 Factors Associated with Risk of Developing Colorectal Cancer

Three-quarters of CRCs occur in people who do not have any particular predisposing factors, and who

are therefore considered to be at average risk. The remaining 25% of patients have hereditary risk

factors that predispose them to the development of CRC: either a well-defined hereditary CRC

syndrome (5%) or a close relative who has been diagnosed with the disease (20%). People with a firstdegree relative with CRC have between a 1.9 and 4.4 relative risk of developing CRC, compared to the

average population. The risk is higher when the affected relative was diagnosed at an early age, or

when several relatives have been affected.16,17 CRC survivors have four times the lifetime risk of

developing a new (metachronous) CRC, compared with people at average risk. The estimated mean

annual incidence of metachronous CRC is 0.3%, with a cumulative incidence of 3.1% at 10 years.18 A

personal history of adenomatous colorectal polyps also increases the risk of CRC, in particular for

patients with larger or multiple polyps and an early age at diagnosis.19

Patients with chronic inflammatory bowel disease, both ulcerative colitis and Crohn disease, are at

increased risk of developing CRC.20,21 The risk increases with the duration of the disease. It is estimated

that, after 10 years of disease, the risk of developing CRC increases by around 1% each year. Thus, it is

estimated that patients with 30 years of inflammatory bowel disease have an 18% risk of developing

CRC. The risk is higher for patients diagnosed with inflammatory bowel disease at an early age, and

with disease extending proximal to the splenic flexure. However, the incidence of CRC in patients with

ulcerative colitis seems to be decreasing. A recent meta-analysis of population-based cohort studies

reported a 1.7 increased risk of CRC among inflammatory bowel disease patients, compared to the

general population, after adjusting for age, gender, and duration of disease.22 These changes are

probably due to more effective treatments and the efficacy of surveillance programs.23

1762

Figure 68-2. Estimated New Cancer Cases and Deaths Worldwide for Leading Cancer Sites by Sex and Level of Economic

Development, 2012 (excluding nonmelanoma skin cancers). (From Torre LA, Bray F, Siegel RL, et al. Global Cancer Statistics,

2012. CA Cancer J Clin 2015;65:87–108.)

1763

Figure 68-3. Mutation frequency across 224 human colorectal cancer samples from The Cancer Genome Atlas. Note the clear

separation of hypermutated (median of 728 nonsilent mutations per tumor) and nonhypermutated (median of 58 nonsilent

mutations). Red, MSI high, CIMP high, or MLH1 silenced; light blue, MSI low, or CIMP low; black, rectum; white, colon; gray, no

data. (From Comprehensive Molecular Characterization of Human Colon and Rectal Cancer. The Cancer Genome Atlas Network.

Nature 2012;487(7407):330–337.)

Patients with type II diabetes have a higher risk of developing CRC compared to the nondiabetic

individual, even when adjusting for factors such as obesity and sedentary lifestyle.24 In addition, CRC

survival rates are lower for diabetic patients compared to nondiabetic patients.25 The relationship

between diabetes and CRC seems to be stronger for men than for women.

MOLECULAR CHARACTERISTICS

2 The traditional model of CRC tumor development is often represented as a linear and sequential

progression from normal epithelium to small adenoma, to large adenoma, to invasive carcinoma, and

finally to metastatic disease.26 This so-called adenoma–carcinoma sequence has been deemed the result

of the progressive accumulation of alterations in the genome. This model has shaped our understanding

of key genetic alterations that result in colorectal tumorigenesis, and has had an enormous clinical

impact by highlighting the importance of screening and surveillance. Whole genome analysis with highthroughput technologies has added new information that is broadening our understanding of colorectal

carcinogenesis. Every CRC has a multitude of distinct genetic alterations that perturb a number of

molecular pathways. This genetic heterogeneity ultimately has a bearing on the speed of growth, local

invasiveness, metastatic potential, and response to therapy. As our understanding of these molecular

changes improves, we anticipate that we will be able to provide better screening and prognostic tools,

and discover new tumor-specific therapies.

The most comprehensive molecular analysis of CRC to date has been conducted by The Cancer

Genome Atlas Consortium.27 They have used state of the art technology to elucidate the mutational

spectrum, the chromosomal and sub-chromosomal changes, the epigenetic regulation and transcriptional

alterations in a large number of CRCs. A key finding that has helped frame our molecular understanding

of CRC is the wide variation in the number of somatic mutations present in most tumors. According to

the number of mutations, CRC can be effectively classified as hypermutated, harboring a median of 728

nonsilent mutations per tumor, and nonhypermutated, with a median of 58 nonsilent mutations (Fig. 68-

3). Nonhypermutated tumors comprise 84% of CRCs, and are characterized by chromosomal instability

(CIN). CIN is the result of missegregation of chromatids in tumor cells, resulting in gains and losses of

entire chromosomes or chromosomal segments; manifesting as aneuploidy and copy number alterations

(CNA).28 Common patterns of aneuploidy and CNAs in nonhypermutated CRC include amplifications in

chromosome arms 1q, 7p and q, 8q, 13q, 17q, and 20p/q, and deletions in 8p, 14q, 15q, 17p, and

18p/q. Some of these CNAs could account for the loss of important tumor suppressors such as TP53 (on

17p), DCC, and SMAD4 (on 18q), and the amplification of oncogenes such as ERBB2 (on 17q). In short,

CIN in nonhypermutated tumors can activate critical oncogenes, and inactivate tumor suppressors that

contribute to the acquisition of tumorigenic traits.

1764