A specific molecular subtype of colorectal cancer is more likely in people with greater obesity and physical inactivity, analyses of prospective data on 861 cancer patients found.
For every 5-kg/m2 increase in body mass index, the likelihood that a biomarker called CTNNB1 would be absent in colorectal cancer tumors increased significantly by 34%. Increasing BMI was not associated with CTNNB1-positive tumors, however, Dr. Teppei Morikawa and his associates reported.
Activity levels were reported as a metabolic equivalent task (MET) score calculated as the metabolic rate for leisure time activities such as walking, specific exercises, sports, or other vigorous activities divided by the resting metabolic rate. MET scores for individual activities were added together as total MET hours per week (MET-h/week). For every 10 MET-h/week increase in activity, the risk of CTNNB1-negative cancer decreased significantly by 7% but the chances of CTNNB1-positive colorectal cancer did not change significantly.
In other words, greater obesity and physical inactivity were associated with significantly higher risk for CTNNB1-negative but not CTNNB1-positive colorectal cancer. This suggests that a person’s energy balance and metabolism affect a specific pathway of carcinogenesis that is different from that of some other colorectal cancer subtypes, reported Dr. Morikawa of the Dana-Farber Cancer Institute, Boston.
The findings were published in the March 1 issue of Cancer Research (2013;73:1600-10).
Previous studies have pointed to the activation of a network of proteins known as the WNT signaling pathway as a critical player in colorectal carcinogenesis. Beta-catenin (CTNBB1) is a major mediator of the WNT pathway, and previous studies have implicated WNT-CTNNB1 signaling in adipogenesis, obesity, glucose metabolism, and metabolic disease. The current findings suggest that energy metabolism affects carcinogenesis in ways that are less dependent on WNT/CTNNB1 activation, Dr. Morikawa reported.
Colon cancer typically is treated as a single disease, and most population-based studies do not consider tumor heterogeneity. Additional epidemiologic studies of the molecular pathology might help identify people who are susceptible to CTNNB1-negative colorectal tumors, determine if CTNNB1 could be a target of treatment, or illuminate prevention strategies for subsets of people, the investigators suggested.
They tapped data on 109,046 women from the Nurses’ Health Study and 47,684 men in the Health Professionals Follow-Up Study to analyze the records of 861 patients who developed rectal and colon cancers between 1986 and 2004 and who had tissue immunohistochemistry data on nuclear CTNNB1 expression.
The current investigators reviewed participants’ medical records and pathology reports and identified deaths from unreported cancers through the National Death Index. They obtained paraffin-embedded tissue blocks from hospitals where participants had undergone tumor resection to confirm colorectal cancer and to conduct immunohistochemistry for CTNNB1 expression. Dr. Morikawa was blinded to other study data when he interpreted the CTNNB1 results in all cases.
The association with higher BMI was seen in subgroups of men or women and in the combined cohort. Compared with patients who had BMIs of 18.5-22.9 kg/m2 , BMIs of 27.5-29.9 kg/m2 were associated with a 77% increased likelihood of CTNNB1-negative colorectal cancer, and BMIs of 30 kg/m2 or greater were associated with an 84% increased risk of CTNNB1-negative cancer.
The analysis of activity levels included 767 patients with activity data whose CTNNB1 status could be determined. Activity level seemed to be associated with lower risk of CTNNB1-negative cancer in subgroups based on sex, but this did not reach statistical significance in men. Combining the two subgroups produced the small but statistically significant 7% lower risk for CTNNB1-negative cancer with increasing levels of physical activity.
An exploratory analysis that combined BMI and activity level suggested that patients with high BMI (25 kg/m2 or greater) and low activity (less than 9 MET-h/week) were 82% more likely to have CTNNB1-negative colorectal cancer compared with patients with low BMI (less than 25 kg/m2) and high activity level (9 or more MET-h/week). BMI and activity level combined were not associated with CTNNB1-positive cancer.
The Cox proportional hazards model used for risk analysis controlled for the effects of other factors that have been associated with colorectal cancer risk, including age; intakes of folate, vitamin D, and calcium; total caloric intake; red meat consumption; smoking status; pack-years of smoking before age 30 years; alcohol intake; use of multivitamins or aspirin; having had a sigmoidoscopy or colonoscopy; family history of colorectal cancer; menopausal status; and use of postmenopausal hormone therapy.
Dr. Morikawa reported having no financial disclosures
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