Obesity and cancer risk and overall and cancer specific mortality: the role of metabolic health and comorbidities

Overweight and obesity are established risk factors for several common cancers such as bowel cancer. However, the number of overweight or obese people in the general population who develop cancer is low. This indicates that there might be sub-groups among overweight/obese individuals, whose cancer risk is modified by factors other than adiposity. Cancer and other chronic diseases often share common risk factors including adiposity, and tend to co-occur within the same individuals. Four in ten patients with cancer have at least one other chronic condition; the most common comorbid conditions include cardiovascular diseases (CVD) and diabetes. Given the biological links between adiposity and the development of these diseases, comorbid conditions may modify cancer processes associated with adiposity.
The overall aim of this project is to investigate whether the occurrence of a major comorbidity, CVD and/or diabetes, prior to cancer modifies associations between obesity and risk of cancer development and death from cancer and other causes.
We will specifically investigate common cancers associated with adiposity, such as bowel cancer and breast cancer (in postmenopausal women), and cancers with a particularly strong association with adiposity and diabetes that include pancreatic cancer and endometrial cancer.
In the full cohort of 500,000 men and women, information collected from participants at recruitment on measurements of anthropometry (weight, height, waist and hip circumference), biomarkers of metabolic health (e.g., levels of glucose, blood lipids), and ascertained comorbidities during follow-up, in particular diabetes and CVD, will be used to assess the relationships between these factors and subsequent cancer outcomes. We will specifically test the hypothesis that for a given level of obesity, as defined by BMI, there are sub-groups of individuals, who are more susceptible to develop cancer and have worse cancer outcomes, because of their perturbed metabolic health and/or co-occurrence of a comorbid condition. To circumvent some of the limitations of conventional epidemiological analyses, we will complement these analyses by an approach termed Mendelian randomization, where genetic proxies will be used instead of the described exposure variables. Additionally, in cancer patients we will assess how these factors are linked to stage at cancer diagnosis, overall and cause-specific mortality.
A better understanding of what underpins variability in cancer outcomes among overweight and obese individuals, could identify important pathways/modifiers of cancer risk.