**2. Personal or family history of sporadic CRCs or adenomatous polyps**

Patients with a personal history of CRC or adenomatous polyps of the colon are at risk for the future development of colon cancer. The clustering of risk in families may be attributed to an inherited susceptibility, common environmental exposures, or a combination of both. The influence of a more distant family history of CRC on individual risk has not been determined with certainty. Some of the increased risk attributed to family history is due to inheritance of known susceptibility genes, such as mutations in the *APC* gene, *p53* gene, or in MMR genes, particularly *MSH2*, *MLH1*, and *MSH6*.

**Protectivefactors** — A large number of factors have been reported by at least some studies to be associated with a decreased risk of CRC. These *include* regular physical activity, a variety of dietary factors, the regular use of aspirin or nonsteroidal antiinflammatory drugs (NSAIDs), and hormone replacement therapy in postmenopausal women. None of these factors are

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Over 50 studies have been conducted to evaluate the influence of physical activity on CRC risk. Overall, the literature is relatively consistent with respect to the effect: Greater physical activity (occupational, recreational, or total activity) is associated with a reduced risk of CRC. The effect is relatively small; the estimated increased risk of colon cancer in the sedentary ranges from 1.6 to 2.0. The biological mechanisms that explain the relationship between physical activity and CRC risk are unclear. Increased physical activity leads to changes in insulin sensitivity and IGF levels, and both insulin and IGF are potentially involved with colorectal carcinogenesis. Additional proposed mechanisms include effects of physical activity on prostaglandin synthesis, effects on antitumor immune defenses, and the reduction in percent body fat associated with exercise. The mechanism is almost certainly multifactorial. Nonetheless, for a host of health-related reasons, frequent moderate to vigorous physical

The effect of dietary intake of fruit and vegetables on CRC risk has been evaluated extensively [22]. Fruits and vegetables are a source of antioxidants, including carotenoids and ascorbate. Other bioactive constituents in fruits and vegetables that may protect against carcinogenesis include the indoles and isothiocyanates. The evidence for an association between fruit and vegetable intake and the risk of CRC is inconsistent [23]. Given this, it is unlikely that a large number of cases of CRC can be attributed directly to a lack of intake of fruits or vegetables, or that major additional interventions to increase consumption would lead to a substantial

There is considerable observational evidence that the use of aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs) has protective effects at all stages of colorectal carcinogenesis (aberrant crypt foci, adenoma, carcinoma, and death from CRC [14]. The mechanism of antineoplastic action of NSAIDs is incompletely understood, but it is believed that both cyclooxygenase (COX)-dependent and COX-independent pathways may be involved. NSAIDs and aspirin may play an important role in secondary chemoprevention of colorectal adenomas and cancer. Because chemopreventive agents must be used in the general popula‐ tion to substantially reduce the burden of disease, the risks of chemoprophylaxis with aspirin or NSAIDs may outweigh the benefits. Serious GI complications occur in regular users of

currently used to stratify CRC screening recommendations.

activity can be recommended to most patients without hesitation.

**3.** Aspirin and Nonsteroidal Anti-inflammatory Drugs

**1.** Physical Activity

**2.** Fruit and Vegetable Intake

reduction in the incidence of CRC.

aspirin and NSAIDs although rare.

Importantly, the majority of cases of CRC cannot be attributed to known genetic defects even when associated with a family history of CRC as recognized genetic syndromes account for only a small proportion of all cases of CRC. Additional autosomal dominant genetic defects conferring a high risk of CRC almost certainly is found. However, at least some of the increased risk of CRC associated with a family history is likely attributable to other genetic factors, such as recessive susceptibility genes, autosomal dominant genes with low penetrance, or complex interactions between an individual's genetic makeup and environmental factors.

Despite the importance of family history on the risk of CRC, up to 25% of individuals with a first-degree relative with confirmed CRC do not report having such a family history and even those that do report a history may not be aware of the increased risk associated with this. This has important implications for the assessment of family history as well as patient and family counseling.
