OBESITY AND COLORECTAL CANCER 

Obesity and physical inactivity have been increasingly linked to colorectal cancer, but a new study suggests that these risk factors are only important in about half of all cases.

The study, published online February 26 in Cancer Research, found that increased body weight and decreased levels of physical activity are only associated with an increased risk for colorectal cancer that tests negative for the biomarker CTNNB1. This subtype accounted for 54% of the cases tested.

For CTNNB1-positive colorectal cancer, which accounted for the remaining 46% of cases tested, no such association was found. It appears that these cancers are independent of those lifestyle factors, senior author Shuji Ogino, MD, PhD, associate professor of pathology at the Dana-Farber Cancer Institute and associate professor of epidemiology at the Harvard School of Public Health in Boston, Massachusetts, told Medscape Medical News.

This finding highlights the importance of tumor heterogeneity, the researchers report. Typically, colorectal cancer is treated as a single disease, but this study shows 2 quite different subtypes.

"If physicians are able to identify individuals who are prone to develop CTNNB1-negative cancer, then it would be possible to strongly recommend physical activity," Dr. Ogino noted.

It might also be possible to develop different treatments for the 2 subtypes, Dr. Ogino explained. The researchers speculate that there is a difference in the way the 2 subtypes react to energy balance, and suggest that an excess energy balance drives the growth of CTNNB1-negative cells.

"For the next step, we should develop targeted chemoprevention and treatment for CTNNB1 and related molecules, which can lower cancer risk and enhance health status, especially in obese individuals," he said.

Both Associations Significant, But Only for 1 Subtype

The researchers analyzed 2 large nationwide prospective studies; data on 109,046 women came from the Nurses' Health Study and data on 47,684 men came from the Health Professionals Study.

CTNNB1 tissue-expression results were available for 861 of the 2263 diagnosed cases of colorectal cancer. Of these tumors, 54% were CTNNB1-negative.

For this subtype, associations were statistically significant for increased body weight and for decreased levels of physical activity, the researchers emphasize.

Higher body mass index (BMI) was associated with a significantly higher risk for CTNNB1-negative colorectal cancer (multivariate hazard ratio (HR) for increments of 5 kg/m², 1.34; P _trend < .0001). Physical activity was associated with a significantly lower risk for CTNNB1-negative colorectal cancer (multivariate HR for increments of 10 MET-h/week, 0.93; P _trend = .044).

Different Reaction to Energy Balance

In a previous study from their laboratory, Dr. Ogino and colleagues found that an excess energy balance had an effect on the progression of CTNNB1-negative colorectal cancer, but not on CTNNB1-positive cancer (JAMA. 2011;305:1685-1694).

"Together with our previous data, our current findings suggest that tumor CTNNB1 status may influence cellular sensitivity to obesity and physical activity not only during progression of an established tumor, but also during earlier steps of tumor development up to clinical detection," they write.

The mechanism may involve insulin and insulin-like growth factors (IGF), which are the main suspects in the search for putative mediators of the causal link between obesity and colorectal cancer. In a number of cell lines, insulin and IGF promote cell survival and proliferation, at least in part through transient activation of the CTNNB1 signaling pathway, the researchers note.

This is the first time that this finding has been reported in such detail, Dr. Ogino told Medscape Medical News. Previous studies have shown an association between increased BMI and an increased risk for microsatellite stable colorectal cancer, but that was just "a conceptual link."

The authors have disclosed no relevant financial relationships.

Cancer Res. Published online February 26, 2013. Abstract