Colorectal Cancer _ ___________________________________________________________________________
was associated with a 41% increase in risk of colorectal cancer [15; 16]. The more pronounced association between current alcohol intake and larger adenomas suggests that alcohol may act during the promotional phase of the adenoma-carcinoma sequence [15; 16]. Cigarette Smoking Cigarette smoking is associated with an increased risk of colorectal cancer incidence and mortality, significantly increased risk of small and large adenomas, adenoma recurrence following polypectomy, and a long cancer induction period (35 years minimum). Rates of colorectal cancer mortality are highest in current smokers, intermediate in former smokers, and lowest in nonsmokers. Increased risk was observed after 20 years of smoking in men and women. Estimates from U.S. data attribute 12% of all colorectal cancer deaths to smoking [17; 18]. Current smoking (vs. never smoking) increases the risk of developing colorectal cancer by 18% [19; 20]. Obesity Obesity, defined as a body mass index (BMI) ≥30, has been consistently associated with increased incidence and mortality from colorectal cancer, particularly in men. Compared with BMI <22, the risk of colorectal cancer increases with a BMI >28.5 by 60% in men and 30% in women. A BMI ≥30 increases the overall risk of colorectal cancer by 45%. The mechanism of increased vulnerability to colorectal cancer in obese patients is not known but may involve the elevated release and bioavailability of growth factors, insulin, and insulin-like growth factor 1. Heightened risk in obese patients appears to be mitigated by high levels of physical activity [21; 22]. BMI is associated with risk of colorectal adenomas and colorectal cancer, but few studies have accrued large enough sample sizes to allow stratified analyses. Evaluation of pooled data from 8,213 participants in seven prospective studies found higher BMI was significantly associated with most histologic characteristics of metachronous adenomas in men, but not in women. The researchers concluded that body mass may affect colorectal carcinogenesis at comparatively early stages, particularly in men [23]. A study of 11,598 survivors of incident primary colorectal cancer examined the effect of obesity on risk of developing a second obesity-associated cancer (e.g., postmenopausal breast, kidney, pancreas, esophageal adenocarcinoma, endometrium). Compared with colorectal cancer survivors of normal prediagnostic BMI, the risk of developing a second obesity- associated cancer was increased 39% in overweight patients and 47% in obese patients [24]. This compares to the risk for developing a first primary obesity-associated cancer, which was increased by 18% in overweight persons and 61% in obese persons. The authors state that colorectal cancer survivors who were overweight or obese before diagnosis had an increased risk of second obesity-associated cancers relative to normal- weight survivors. Elevated risk of developing a second cancer in colorectal cancer survivors is more likely the result of the
increased prevalence of overweight and obesity rather than increased susceptibility [24]. Researchers have associated a common mutation in colorectal cancer with elevated risk of metabolic disease. APC is a tumor- suppressor gene that indirectly regulates cell proliferation by encoding a protein called beta-catenin. APC inactivation by mutation leads to loss of beta-catenin function, which results in unchecked cellular replication and other processes that drive progression to malignant phenotype. Activation of the Wnt signaling pathway, normally mediated by beta-catenin, also occurs. Beta-catenin-Wnt signaling is involved in glucose metabolism and metabolic diseases such as obesity and type 2 diabetes. Using a molecular pathologic epidemiology database, researchers found that risk of beta-catenin-negative colorectal cancer was significantly higher with greater BMI and lower with increased physical activity level. Risk of beta-catenin- positive colorectal cancer was unrelated to BMI or physical activity level [25]. Factors Associated with a Decreased Risk of Colorectal Cancer Polyp Removal Removal of adenomatous polyps significantly reduces the risk of colorectal cancer. This will be discussed in detail later in this course. Physical Activity A sedentary lifestyle has been associated with an increased risk of colorectal cancer, although this finding has not been consistent [14]. More consistent is the association between regular physical activity and a decreased incidence of colon but not rectal cancer, with an estimated 22% to 27% risk
reduction [26; 27; 28; 29]. Diet Low in Fat and Meat
Colon cancer rates are high in populations with high total fat intakes and are lower in those consuming less fat [30]. On average, fat comprises 40% to 45% of total caloric intake in high-incidence Western countries; in low-risk populations, fat accounts for only 10% of dietary calories [31]. Several case- control studies have explored the association of colon cancer risk with meat or fat consumption as well as protein and energy intake [32]. Positive associations with meat consumption or fat intake have been found frequently but have not always achieved statistical significance [33]. One hypothesis is that heterocyclic amines formed when meat or fish are cooked at high temperatures may contribute to the increased risk of colorectal cancers associated with meat consumption observed in epidemiologic studies [34; 35]. Diet High in Fiber Despite evidence from case-control studies of a protective effect, results from a large prospective study found no difference in the risk of colorectal cancer between women in the highest quintile group compared with the lowest quintile group with
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