Colorectal Cancer

Obesity has also been consistently associated with higher risk of colorectal cancer in men (relative risks of approx 1.5 to 2.0) and women (relative risks of approx 1.2 to 1.5) in both case-control and cohort studies (Table 3) (18,34,35,94,95). In studies that were able to examine the colon and rectum separately, relative risks have been generally higher for the colon (18,36,96). Similar relationships are seen for colon adenomas, with stronger associations observed between obesity and advanced adenomas (97-100).

A gender difference, in which obese men are more likely to develop colorectal cancer than obese women, has been observed consistently across studies and populations. The reasons for this gender difference are speculative. One hypothesis is that central adiposity, which occurs more frequently in men, is a stronger predictor of colon cancer risk than peripheral adiposity or general overweight. Support for the role of central obesity in colo-rectal cancer comes from studies reporting that waist circumference and WHR are related strongly to risk of colorectal cancer and large adenomas in men (101). Two recent prospective cohort studies specifically examining the predictive value of anthropometric measurements for risk of colon cancer found waist circumference (102) or WHR (103) to be associated with colon cancer risk, independent of, and with greater magnitude than, BMI, and this result was seen in women as well as in men. However, the association between WHR and colorectal cancer in women was not stronger than the association between BMI and colorectal cancer in other studies that examined both measures (104,105), making it less likely that body fat distribution completely explains the gender differences.

Another explanation is that there might be an offsetting beneficial effect of obesity on colorectal cancer risk in women based on evidence that exogenous estrogens (in the form of postmenopausal hormone therapy) reduce the risk of colorectal cancer in women (106,107). However, this hypothesis also is quite speculative, as circulating levels of endogenous estrogens are higher in obese men as well as obese women, compared with lean subjects (108) and oral intake of exogenous estrogens could have different effects than endogenous estrogens on the risk of colon cancer.

Giovannucci was the first to propose the mechanistic hypothesis that high body mass, and central obesity in particular, increased colon cancer risk through their effect on insulin production (101,109,110). Insulin and IGFs have been shown to promote the growth of colonic mucosal cells and colonic carcinoma cells in in vitro studies

  • 111.112). This hypothesis has received recent support from many epidemiological studies. Higher risk of colorectal cancer has been associated with elevated fasting plasma glucose and insulin levels following a standard dose of oral glucose challenge
  • 101.113) and with elevated serum insulin or C-peptide levels (114-116). Several prospective cohort (114,117,118) and case-control studies (115,119,120) have found increased risk of colorectal cancer and large adenomas with increasing absolute levels of IGF-I and decreasing levels of IGFBP-3. A recent meta-analysis of six case-control and nine cohort studies found diabetes mellitus, which is preceded by many years of hyperinsulinemia, to be associated with a 30% increase in risk of colorectal cancer (121). Elevated levels of serum leptin recently have been found to be associated with increased risk of colon cancer, independent of circulating insulin levels (122,123). Low levels of plasma adiponectin have also been found to be associated with increased risk of colorectal cancer (124) and colorectal adenoma (125).

There are very few studies examining the impact of adiposity on prognosis among colorectal cancer patients. Available studies suggest that adiposity may have an adverse effect on prognosis (126-128), although results are somewhat inconsistent by gender and for colon rectal cancer.

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