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Obesity linked to risk for molecular subtype of colorectal cancer
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Evidence has suggested that metabolic diseases such as obesity and type 2 diabetes are affected by a genetic and functional variation in the WNT/beta-catenin, or CTNNB1 signaling pathway. In a recent study, researchers suggest that obesity and physical inactivity are associated with risk for a molecular subtype of colorectal cancer.
“We know that exercise and avoiding obesity decrease colorectal cancer risk, but little is known about why,” researcher Shuji Ogino, MD, PhD, associate professor of pathology at Dana-Farber Cancer Institute and associate professor of epidemiology at Harvard School of Public Health, said in a press release. “In this study, we used a biomarker named CTNNB1, which is a molecule implicated in cancer and obesity, to divide patients into two groups, CTNNB1-positive and CTNNB1-negative.”
Shuji Ogino
In their clinical follow-up of 109,046 women in the Nurses’ Health Study and 47,684 men in the Health Professional’s Follow-up Study, the researchers discovered 861 incidents of rectal and colon cancers with tissue immunohistochemistry data on the nuclear biomarker, CTNNB1 expression, they wrote.
According to data, greater BMI was linked to a significantly higher risk for CTNNB1-negative cancer (multivariate HR=1.34; 95% CI, 0.92-1.25 for 5 kg/m2 increment), but not with CTNNB1-positive cancer risk (multivariate HR=1.07; 95% CI, 0.92-1.25 for 5 kg/m2 increment, between CTNNB1-negative and CTNNB1-positive risks), they wrote.
Moreover, physical activity levels were related to a lower risk for CTNNB1-negative cancer (multivariate HR=0.93; 95% CI, 0.87-1 for 10 MET-hours per week increment), but not with CTNNB1-positive cancer risk (multivariate HR=0.98; 95% CI, 0.91-1.05 for 10 MET-hours per week increment).
“Our results provide additional evidence for a causal role of obesity and a physically inactive lifestyle in a specific molecular subtype of colorectal cancer,” Ogino said in the release. “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.”
Therefore, the researchers suggest energy balance and metabolism status employed the effect in a specific carcinogenesis pathway which is less likely dependent on WNT/CTNNB1 activation. These findings hold potential for developing improved cancer prevention strategies, they wrote.
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Christos Mantzoros, MD, DSc, PhD h.c.
Obesity, the prevalence of which is rising to epidemic proportions in Western societies, has clearly been associated with the development of certain malignancies, including colorectal cancer. Dysregulation of the WNT-CTNNB1 (beta-catenin) signaling pathway has also been implicated in the pathogenesis of colorectal carcinoma and metabolic diseases. This study utilized a “Molecular Pathological Epidemiology” approach to address the hypothesis that the status of CTNNB1 in colonic cells might influence cellular sensitivity to the status of energy balance.
The investigators utilized data from 109,046 women and 47,684 men enrolled in two US nationwide prospective cohort studies. The study reports BMI, the most widely used index of obesity, and physical inactivity were associated with increased risk for CTNNB1-negative colorectal cancer, but not with that of CTNNB1-positive cancer. Thus, these data suggest that energy balance status may exert its effect through a specific carcinogenic pathway that is less likely to depend on CTNNB1 activation. Several other pathways, including the adiponectin and insulin-like growth factor I (IGF-I) pathway, have been proposed to link obesity with colorectal cancer and experimental evidence indicates that their effect may be independent from the WNT-CTNNB1 (beta-catenin) signaling pathway.
The main strengths of the study are its large size and its novel approach (i.e. a Molecular Pathological Epidemiology approach), which, by involving the integration of molecular pathology and epidemiology, has been suggested to be a powerful research design to investigate potential cancer mechanisms and to study the influence of environmental and lifestyle exposures at the population level. Limitations of the study include its observational nature that precludes claims on proof of causality as well as the fact that only one molecule of the pathway of interest was examined.
Future observational and interventional studies are needed to fully elucidate the molecular pathways leading from obesity to colorectal cancer. Elucidation of these molecular pathways and study of possible interplays between such pathways and environmental factors including diet and exercise could lead to the development of novel preventive and therapeutic strategies which could provide tangible benefits to obese patients.
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