Obesity, metabolic dysfunction, and the risk of obesity-related cancer

Excess body fat, diabetes, and metabolic syndrome are associated with certain types of cancers. Although obesity is strongly associated with metabolic dysfunction (MetDys), some overweight individuals do not develop MetDys, although certain lean individuals do. The objective of this dissertation was to determine whether MetDys modifies the effect of excess body fat on cancer risk. The independent and combined effects of body mass index (BMI), waist circumference (WC), and MetDys on obesity-related cancer (ObCa) risk was examined among 3,818 45--69 year-olds in the Framingham Offspring Study using Cox proportional hazard's analysis. Primary ObCa types included postmenopausal breast, endometrial, and colon cancer. Markers of MetDys included fasting glucose, triglycerides, high density lipoprotein-cholesterol, and hypertension. Subjects with ?2 metabolic abnormalities were considered to have prevalent MetDys. Obesity alone (BMI?30) in both men and women led to about a two-fold increased risk of ObCa. WC and waist-to-height ratio (WHtR) were somewhat stronger risk predictors in men than in women. There was little evidence of effect modification of WC or WHtR by MetDys in either men or women. In obese men, however, prevalent MetDys was associated with a 2.5-fold increased risk (95% CI: 1.36--1.46) of ObCa while obese men without MetDys had only a non-statistically significant 1.5-fold increased risk (0.70--3.03). There was no effect modification in women. To separate the effects of overall body fat from fat distribution, hip circumference was added to the multivariable models. Here, the effect of a WC >40 inches in men was strengthened (HR=2.59; 95% CI: 1.53--4.36) by controlling for HC. Conversely, when controlling for WC, the smallest HC in men conveyed a higher cancer risk (HR=2.68; 95%CI: 1.46--4.89). Subjects gaining ≥1 lb/year over approximately 14 years and who developed MetDys during that period had a 77% (95%CI: 1.21--2.59) increased ObCa risk while weight gainers not developing MetDys had a 31% (95%CI: 1.00--1.71) increased risk. Finally, weight gainers who became overweight/obese had a higher cancer risk than those with long-term overweight/obesity. This study suggests that those with excess body fat and long-term weight gain have higher ObCa risk, with little evidence that metabolic abnormalities modified the effect of obesity.