Natural History of Colorectal Cancer
Molecular Events Associated With Colon Carcinogenesis
Family History as a Risk Factor for Colorectal Cancer
Inheritance of Colorectal Cancer Predisposition
Difficulties in Identifying a Family History of Colorectal Cancer Risk
Other Risk Factors for Colorectal Cancer
Interventions
        State of the Evidence Base
        Rationale for Screening
        Identification of Persons at High Genetic Risk of Colorectal Cancer
Primary Prevention of Familial Colorectal Cancer
        Chemoprevention
        Modifying Behavioral Risk Factors

Colorectal cancer is a commonly diagnosed cancer in both men and women. In 2004, an estimated 146,940 new cases will be diagnosed, and 56,730 deaths from colorectal cancer will occur.[1] Two kinds of observations indicate a genetic contribution to colorectal cancer risk: (1) increased incidence of colorectal cancer among persons with a family history of colorectal cancer; and (2) families in which multiple family members are affected with colorectal cancer, in a pattern indicating autosomal dominant inheritance of cancer susceptibility.[2-6] About 75% of patients with colorectal cancer have sporadic disease, with no apparent evidence of having inherited the disorder. The remaining 25% of patients have a family history of colorectal cancer that suggests a genetic contribution, common exposures among family members, or a combination of both. Genetic mutations have been identified as the cause of inherited cancer risk in some colon cancer-prone families; these mutations are estimated to account for only 5% to 6% of colorectal cancer cases overall. It is likely that other undiscovered major genes and background genetic factors contribute to the development of colorectal cancer, in conjunction with nongenetic risk factors.

Colorectal tumors present with a broad spectrum of neoplasms, ranging from benign growths to invasive cancer and are predominantly epithelial derived tumors (i.e., adenomas or adenocarcinomas). Pathologists have classified the lesions into 3 groups: nonneoplastic polyps, neoplastic polyps (adenomatous polyps, adenomas), and cancers. While most adenomas are polypoid, flat and depressed lesions may be more prevalent than previously recognized. Large flat and depressed lesions may be more likely to be severely dysplastic.[7] Specialized techniques may be needed to identify, biopsy, and remove such lesions.[8] The nonneoplastic polyps include hyperplastic, juvenile, inflammatory, and lymphoid polyps. They have not generally been thought of as precursors of cancer. Research, however, suggests increased colorectal cancer risk in some families with multiple members affected with juvenile polyposis and hyperplastic polyposis.[9-11]

Epidemiologic studies have shown that a personal history of colon adenomas places one at increased risk of developing colon cancer.[12] Two complementary interpretations of this observation are (1) the adenoma may reflect an innate or acquired tendency of the colon to form tumors; and (2) adenomas are the primary precursor lesion of colon cancer. Over 95% of colorectal cancers are carcinomas, and about 95% of these are adenocarcinomas. It is well recognized that adenomatous polyps are benign tumors that may undergo malignant transformation. They have been classified into 3 histologic types, with increasing malignant potential: tubular, tubulovillous, and villous. While there is no direct proof that the majority of colorectal cancers arise from adenomas, adenocarcinomas are generally considered to arise from adenomas,[13-17] based upon these important observations: (1) benign and malignant tissue occur within colorectal tumors;[18] and (2) when patients with adenomas were followed for 20 years, the risk of cancer at the site of the adenoma was 25%, a rate much higher than that expected in the normal population.[19] Also, 3 characteristics of adenomas that are highly correlated with the potential to transform into cancer include large size, villous pathology, and the degree of dysplasia within the adenoma.[18] In addition, removal of adenomatous polyps is associated with reduced colorectal cancer incidence.[19,20]

The transition from normal epithelium to adenoma to carcinoma is associated with acquired molecular events.[21-23] This tumor progression model was deduced from comparison of genetic alterations seen in normal colon epithelium, adenomas of progressively larger size, and malignancies.[24,25] At least 5 to 7 major deleterious molecular alterations may occur when a normal epithelial cell progresses in a clonal fashion to carcinoma. There are at least 2 major pathways by which these molecular events can lead to colorectal cancer. About 85% of colorectal cancers are due to events that result in chromosomal instability (CIN) and the remaining 15% are due to events that result in microsatellite instability (MSI or MIN, also known as replication error (RER)).[23,26,27]

Key changes in CIN cancers include widespread alterations in chromosome number (aneuploidy) and detectable losses at the molecular level of portions of chromosome 5q, chromosome 18q, and chromosome 17p; and mutation of the KRAS oncogene. The important genes involved in these chromosome losses are APC(5q), DCC/MADH2/MADH4(18q), and TP53(17p) respectively,[22,28] and chromosome losses are associated with instability at the molecular and chromosomal level.[23] Among the earliest events in the colorectal tumor progression pathway is loss of the APC gene, which appears to be consistent with its important role in predisposing persons with germline mutations to colorectal tumors. Acquired or inherited mutations of DNA damage repair genes also play a role in predisposing colorectal epithelial cells to mutations. The type of mutation may influence the rate or type of pathologic change in the tumors. Not every tumor acquires every mutation and the order in which mutations are acquired is not necessarily consistent. The type of mutations the tumor acquires may influence the rate of tumor growth or type of pathologic change in the tumors.[28] For example, the rate of adenoma to carcinoma progression appears to be faster in microsatellite unstable tumors compared with microsatellite stable tumors. Characteristic histologic changes such as increased mucin production can be seen.

The key characteristics of MSI cancers are tumors with largely intact chromosome complement, but acquisition of defects in DNA repair, such that mutations that may occur in important cancer-associated genes are allowed to persist. These types of cancers are detectable at the molecular level by alterations in repeating units of DNA that occur normally throughout the genome, known as a DNA microsatellite. Mitotic instability of microsatellites is the hallmark of MSI cancers.

The knowledge derived from the study of inherited colorectal cancer syndromes provided important clues to the development of tumor progression in people without germline abnormalities. Among the earliest events in the colorectal tumor progression pathway (both MSI and CIN) is loss of function of the APC gene product, which appears to be consistent with its important role in predisposing persons with germline mutations to colorectal tumors. Acquired or inherited mutations of DNA damage-repair genes also play a role in predisposing colorectal epithelial cells to mutations.

Among the earliest studies of family history of colorectal cancer were those of Utah families that reported a higher number of deaths from colorectal cancer (3.9%) among the first-degree relatives of patients who had died from colorectal cancer, compared with sex-matched and age-matched controls (1.2%).[29] This difference has since been replicated in numerous studies that have consistently found that first-degree relatives of affected cases are themselves at a 2-fold to 3-fold increased risk of colorectal cancer. Despite the various study designs (case-control, cohort), sampling frames, sample sizes, methods of data verification, analytic methods, and countries where the studies originated, the magnitude of risk is consistent.[30-35]

Using data from a cancer family clinic patient population, the relative and absolute risk of colorectal cancer for different family history categories was estimated (Table 1).[36,37]

When the family history includes 2 or more relatives with colorectal cancer, the possibility of a genetic syndrome is increased substantially. The first step in this evaluation is a detailed review of the family history, to determine the number of relatives affected, their relationship to each other, the age at which the colorectal cancer was diagnosed, the presence of multiple primary colorectal cancer, and the presence of any other cancers consistent with an inherited colorectal cancer syndrome. (See the section on Major Genetic Syndromes below.)

Several genes associated with colorectal cancer risk have been identified; these are described in detail in the Colon Cancer Genes section of this summary. Almost all gene mutations known to cause a predisposition to colorectal cancer are inherited in an autosomal dominant fashion.[2] Thus, the family characteristics that suggest autosomal dominant inheritance of cancer predisposition are important indicators of high risk and of the possible presence of a cancer-predisposing mutation. These include the following:

1. Vertical transmission of cancer predisposition. (Vertical transmission refers to the presence of a genetic predisposition in sequential generations.)



2. Inheritance risk of 50% for both males and females. When a parent carries an autosomal dominant genetic predisposition, each child has a 50% chance of inheriting the predisposition. The risk is the same for both male and female children.



3. Other clinical characteristics also suggest inherited risk:
   • Cancers in people with an autosomal dominant predisposition typically occur at an earlier age than sporadic (nongenetic) cases.
   • An autosomal dominant predisposition to colorectal cancer may include a predisposition to other cancers, such as endometrial cancer, as detailed in the Major Genetic Syndromes section of this summary.
   • In addition, 2 or more primary cancers may occur in a single individual. These could be multiple primary cancers of the same type (e.g., 2 separate primary colorectal cancers) or primary cancer of different types (e.g., colorectal and endometrial cancer in the same individual).

Hereditary colorectal cancer has 2 well-described forms: familial adenomatous polyposis (FAP, including an attenuated form of polyposis, AFAP), due to germline mutations in the APC gene,[38-45] and hereditary nonpolyposis colorectal cancer (HNPCC), which is caused by germline mutations in mismatch repair (MMR) genes.[46-49] Many other families exhibit aggregation of colorectal cancer and/or adenomas, but with no apparent association with an identifiable hereditary syndrome, and are known collectively as familial colorectal cancer (FCC).[2]

The accuracy and completeness of family history data must be taken into account in using family history to assess individual risk in clinical practice, and in identifying families appropriate for cancer research. A reported family history may be erroneous, or a person may be unaware of relatives with cancer.[50] In addition, small family sizes and premature deaths may limit how informative a family history may be. Also, some persons may carry a genetic predisposition to colorectal cancer but do not develop cancer, giving the impression of “skipped” generations in a family tree.

When family histories of colon cancer were checked in a research study, a sensitivity of 73% (95% confidence interval (CI) 54%-86%) was obtained.[51] In this study of Utah patients, the investigators compared self-reported family history of colon cancer to a computerized Utah Population Database, which was created by linking genealogical records with the state cancer registry. The kappa score, a measure of overall agreement between the reported family history and the database, was 0.56 (95% CI 0.45-0.66), indicating moderately good agreement. Thus, what patients tell clinicians about their family histories is a reasonably good indicator of actual history.

Other risk factors that may influence the development of adenomatous polyps and colorectal cancer risk include diet, use of nonsteroidal anti-inflammatory drugs, postmenopausal hormone use, cigarette smoking, colonoscopy with removal of adenomatous polyps, and physical activity.

• Dietary factors that appear to be associated with developing adenomatous polyps and an increased incidence of colorectal cancer risk include a diet high in total fat,[52-54] and meat (both red and white meat).[54-65]
• Some [66-68] but not all [69] studies have reported an association between aspirin use and decreased adenomatous polyp development and colon cancer incidence. In addition, studies have suggested a decreased risk of colon cancer among users of postmenopausal female hormone supplements.[70,71]
• Cigarette smoking is associated with an increased tendency to form adenomas and develop into colorectal cancer.[72,73]
• Colonoscopy with removal of adenomatous polyps may reduce the risk of colorectal cancer.[74]
• A sedentary lifestyle has been associated in some,[75-77] but not all,[78] studies with an increased risk of colorectal cancer.

(Refer to the PDQ Summary on Prevention of Colorectal Cancer for more information.)

Genetic factors appear to influence the age of onset of colorectal cancer. People who have a first-degree relative with colorectal cancer are estimated to have an average onset of colorectal cancer about 10 years earlier than people with sporadic colorectal cancer.[30] The increased cancer risk conferred by a family history of colorectal cancer appears to manifest itself primarily in people under age 60.[30] Markedly early onset of cancer is seen in hereditary conditions conferring an increased risk of colorectal cancer with a mean age of diagnosis of colorectal cancer in the early 30s for FAP and 40s for HNPCC.[2,3]

For the most part, the effects of other nongenetic risk factors have not been evaluated in people who are genetically susceptible to colorectal cancer. Studies of carcinogen metabolic polymorphisms, such as glutathione-s transferase and N-acetyl transferase, suggest that there may be some influence on risk of colorectal cancer, through interactions with micronutrients or other environmental factors; however, these data are too preliminary to apply in a clinical setting.[55,79-81]

In practical terms, knowing that a person is at increased risk of colorectal cancer because of a germline abnormality is most useful if the knowledge can be used to prevent the development of cancer or cancer-related morbidity and mortality once it has developed. While one can also use the information for family planning, decisions about work and retirement, and other important life decisions, prevention is usually the central concern.

This section covers screening: testing in the absence of symptoms for colorectal cancer and its precursors (i.e., adenomatous polyps) to identify people with an increased probability of developing colorectal cancer. Those with abnormalities should undergo diagnostic testing to see if they have an occult cancer, followed by treatment if cancer or a precursor is found. Taken together, this set of activities is aimed at either preventing the development of colorectal cancer by finding and removing its precursor, the adenomatous polyp, or preventing complications by early detection and treatment.

Primary prevention, eliminating the causes of colorectal cancer in people with genetically increased risk, is addressed later in this section.

Currently there are no published randomized controlled trials of screening in people with genetically increased risk of colorectal cancer and few controlled comparisons. While a randomized trial with a no-screening arm is not feasible, there is a need for well-designed studies comparing various screening methods or differing periods of time between screening procedures. A published observational study that compared screened with unscreened (by choice) “controls” evaluated a 15-year experience with 252 relatives at risk for hereditary nonpolyposis colorectal cancer, 119 of whom declined screening. Eight of 133 (6%) in the screened group developed colorectal cancer, compared with 19 in the unscreened group (16%, P=.014).[82] In general, however, people with genetic risk have been excluded from the trials of colorectal cancer screening that have been published thus far, so it is not possible to estimate effectiveness by subgroup analyses. Therefore, prevention in these patients cannot be based on strong evidence of effectiveness, the kind ordinarily relied on for recommendations by expert groups when they suggest guidelines.

Given these considerations, clinical decisions are based by default on clinical judgment. These decisions take into account the biologic and clinical behavior of each kind of genetic condition, as well as possible parallels with patients at average risk, for whom screening is known to be effective.

The evidence base for the effectiveness of screening in average-risk people (those without apparent genetic risk) is the benchmark for considering an approach to people at increased risk. (Refer to the PDQ summary on Screening for Colorectal Cancer for more information.) In average-risk people, screening programs based on several different kinds of tests have been shown, with various degrees of persuasiveness, to prevent death from colorectal cancer:[19]

• Fecal occult blood testing (FOBT) is supported by 3 randomized controlled trials.[83-85]
• Sigmoidoscopy screening is supported by 4 case-control studies.[20,86-88]
• Colonoscopy has been shown to be effective in reducing the incidence of colorectal cancer in 2 cohort studies of patients with adenomatous polyps.[74,89]
• Double-contrast barium enema may be effective, considering that it allows examination of the entire bowel, but has low sensitivity for large polyps and cancers.[19]

The fact that screening of average-risk persons reduces the risk of dying from colorectal cancer forms the basis for recommending screening in persons at high increased genetic risk of colorectal cancer. As logical as this approach seems, it is important to keep in mind that randomized trials of screening have not been performed in this special population. It is also important to note that observational studies performed on families with HNPCC [90,91] and FAP [92] support the value of screening. These studies suggest a stage shift towards earlier stages and a probable reduction in colorectal cancer mortality among screen-detected cancers.

Widely accepted criteria (1–3 below) for appropriate screening apply as much to diseases with a strong (more than 1 affected first-degree relative or 1 first-degree relative diagnosed at younger than 60 years) genetic component as they do to other diseases.[93,94] Additional criteria (4 and 5) were added below.[95]

1. A high burden of suffering, in terms of morbidity, mortality, and loss of function.
2. A screening test that is sufficiently sensitive, specific, safe, convenient, and inexpensive.
3. Evidence that treating the condition when it is detected early, by screening, results in a better prognosis than treatment after it is detected because of symptoms.
4. Evidence on the extent to which screening test and treatment do harm.
5. The value judgment that the screening test does more good than harm.

Of these criteria, the first and second are satisfied in genetically determined colorectal cancer. The harms of screening (criterion 4), especially major complications of diagnostic colonoscopy (perforation and major bleeding) are also known. Proof that early intervention results in better outcomes (criterion 3) is limited, but suggests benefit. One study in the setting of hereditary nonpolyposis colorectal cancer found earlier stage/local tumors in the screened individuals.[82]

Clinical criteria may be used to identify persons who are candidates for genetic testing to determine whether an inherited susceptibility to colorectal cancer is present. These criteria include:

• A strong family history of colorectal cancer and/or polyps.
• Multiple primary cancers in a patient with colorectal cancer.
• Existence of other cancers within the kindred consistent with known syndromes causing an inherited risk of colorectal cancer, such as endometrial cancer.
• Early age at diagnosis of colorectal cancer.

When such persons are identified, options tailored to the patient situation are considered. (See the Major Genetic Syndromes section of this summary for information on specific interventions for individual syndromes.)

At this time, the use of mutation testing to identify genetic susceptibility to colorectal cancer is not recommended as a screening measure in the general population. The rarity of mutations in the APC- and HNPCC-associated MMR genes, and the limited sensitivity of current testing strategies, render general population testing potentially misleading and not cost effective.

Observational studies of average-risk people have suggested that the use of some drugs and supplements (nonsteroidal anti-inflammatory drugs [NSAIDs], estrogens, folic acid, and calcium) might prevent the development of colorectal cancer.[96] (Refer to the PDQ summary on Prevention of Colorectal Cancer for more information.) None of the evidence is so convincing as to lead expert groups to recommend these drugs and supplements specifically to prevent colorectal cancer, and few studies specifically enrolled people with an inherited predisposition for colorectal cancer. Although antioxidants are hypothesized to prevent cancer, a randomized controlled trial of antioxidant vitamins (beta carotene, vitamin C, vitamin E) has shown no effect on colorectal cancer incidence.[97]

Randomized controlled trials have shown that NSAIDs (sulindac and celecoxib) induce regression of adenomas in patients with familial adenomatous polyposis.[98,99] However, in a small study of pediatric patients who were APC gene mutation carriers and who had not yet developed adenomas, sulindac did not yield a significant reduction in adenoma incidence.[100] These drugs may act by inhibiting cyclo-oxygenase II (COX-2), and therefore the production of prostaglandins, both of which are found in higher concentrations in colorectal cancers than in normal mucosa.[101] They may also act through COX-2 independent pathways that trigger programmed cell death.[102] The NSAID effect apparently stops when the drugs are stopped. The results of these trials are consistent with observational studies showing that aspirin is a protective factor for colorectal cancer.[103] No randomized trial has shown that NSAIDs prevent deaths from colorectal cancer, however, and at least one prospective study showed no association between aspirin use and the incidence of colorectal cancer. The authors concluded “the low dose of aspirin used and the short treatment period may account for the null findings.”[69] Other prospective studies showed a significant reduction in colorectal cancers in health care workers who regularly used aspirin.[104,105] A randomized, double-blind, placebo-controlled trial in patients who had a personal history of colon adenomas showed a modest but statistically significant reduction in the incidence of colonic adenomas with daily aspirin use.[68] In a double-blind placebo study, daily aspirin use was also associated with reduction in the incidence of colorectal adenomas in patients with previous colorectal cancer.[106] Less is known about the effects of NSAIDs on polyp development in people with other kinds of familial cancer syndromes such as HNPCC and familial aggregation.

Use of folic acid supplements for more than 15 years has been shown in one observational study to be associated with a 75% lower colorectal cancer rate (relative risk (RR) 0.25, 95% CI 0.13-0.51).[59] It is hypothesized that since folate is required for DNA synthesis, suboptimal amounts might cause abnormalities in DNA synthesis or repair. Randomized controlled trials are under way to test the hypothesis that folic acid supplements prevent cardiovascular disease (through their effect on homocysteine). They may, when completed, have enough statistical power, singly or together, to provide stronger evidence on the effect of folic acid supplements on colorectal cancer.

It has been suggested that calcium, by binding bile acids in the bowel lumen, might inhibit their carcinogenic effects.[58,107] A randomized controlled trial of calcium supplementation, 1,200 mg of elemental calcium daily for 4 years, reduced the risk of recurrent adenomas in presumably average-risk people with adenomas by 19% (adjusted risk ratio 0.81, 95% CI 0.67-0.99).[58] It is uncertain whether this finding applies to people with genetically increased risk of colorectal cancer. Similarly, the observational evidence that estrogens are associated with a lower incidence of colorectal cancer does not include information specifically about people with a genetically increased risk of colorectal cancer.[70,108-110]

There may be other reasons for taking drugs such as aspirin and folic acid to prevent cardiovascular disease or calcium and estrogens to prevent osteoporosis. But if they are taken solely to prevent colorectal cancer, users should understand that the current evidence is not strong. In the case of NSAIDs, there is a small risk of bleeding complications such as stroke and upper gastrointestinal ulceration and bleeding to balance against the possibility of benefit.

Level of evidence for NSAIDs in FAP: 3a

Level of evidence for other risk groups and interventions: 6

Several components of diet and behavior have been suggested, with various levels of consistency, to be risk factors for colorectal cancer. (Refer to the PDQ summary on Prevention of Colorectal Cancer for more information.) These lifestyle factors may represent potential means of prevention.[96,110,111] Expert groups differ on the interpretation of the evidence for some of these components.

Little is known about whether these same factors are protective in people with genetically increased risk of colorectal cancer. In one case-control study of this question, physical activity, high energy, and low vegetable intake were significantly related to cancer risk in people with no family history of colorectal cancer but showed no relationship in people with a family history, despite adequate statistical power to do so.[112] One observational study has shown that use of multivitamins and folate in women with a family history of colorectal cancer was associated with decreased relative risk of colon cancer.[113]

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