Background:
While obesity is an established risk factor for a number of common cancers,1 the predictive power of BMI (body mass index) and other adiposity indices in cancer risk prediction remains moderate in the general population.2 This suggests that some heterogeneity might exist regarding the increased risk of cancer related to adiposity.
Cancer and other chronic diseases often share common risk factors including adiposity, and tend to co-occur within the same individuals.3 Four in ten patients with cancer have at least one other chronic condition; the most common comorbid conditions include cardiovascular disease (CVD) and type-2 diabetes (T2D).4
One hallmark of obesity is systemic inflammation, a well-described pathway for the development of cancer,5 CVD,6 and T2D.7 Comorbid conditions may modify cancer processes associated with obesity through shared pathways, for example, by synergistically stimulating inflammation, but also through additionally activated pathways or external factors such as disease treatment.
The extent to which a comorbidity might contribute to cancer risk among overweight individuals is unclear.
Obesity has also been linked to poorer survival in cancer patients.8 Similarly, patients diagnosed with cancer who have pre-existing comorbidities such as diabetes are at increased risk for all-cause mortality compared with those without diabetes.9
However, the interplay between obesity and comorbidities on cancer development and survival is uncertain.
Hypothesis and objectives:
Our hypothesis is that the occurrence of a major comorbidity, CVD and/or T2D, prior to cancer modifies associations between obesity and risk of cancer development and cancer mortality.
Specific objectives:
1. To investigate whether incident CVD or T2D modifies the association between obesity and the risk of developing ‘obesity-related’ cancers, and specifically of the colorectum, pancreas, postmenopausal breast, and endometrium;
2. To investigate causal associations of in turn, CVD and T2D, by obesity status with cancers of the colorectum, pancreas, postmenopausal breast, and endometrium using Mendelian randomization (MR) approaches;
3. To investigate the role of obesity in cancer progression in relation to pre-existing comorbidities.
Settings and methods:
We will use individual-level data from large cohorts in Europe and Asia, complemented with a population-based primary care database and data from genetic consortia. Requirements include the availability of incident data on CVD and/or T2D. Treatment data for comorbidities and cancer will also be incorporated.
For risk of cancers, we will use survival models with age as the main time scale, time-varying variables for incident CVD/T2D, and an interaction with obesity (BMI).
Among cancer patients, survival models with time since diagnosis of cancer as the main time scale will be used with interactions between obesity and the presence of comorbidities prior to cancer.
Cancer risks will be related to obesity in the presence/absence of comorbidity in objective 1, while for objective 2, we will compare cancer risk related to comorbidity (using MR and GWAS data for susceptibility to CVD/T2D and related traits) in the presence/absence of obesity. The evaluation will address the question whether obesity and comorbidities interact in relation to cancer risk.
Impact:
This project could identify important pathways/modifiers of cancer risk among overweight individuals and lead to a more stratified approach to preventive or management strategies.