Investigation of obesity paradox for renal cell cancer: a multilevel approach from molecular to neighborhood impacts

PROJECT SUMMARY The incidence of renal cell cancer (RCC) has been steadily increasing over the past three decades in the U.S. and it remains the most lethal urological malignancy due to a lack of screening for early detection. While excess body adiposity at the individual level is a recognized modifiable risk factor for RCC, the influences of obesogenic factors beyond individual level, particularly the molecular mechanisms and neighborhood environments, remain unexplored. In addition, the impact of body adiposity on RCC survival is debated, with evidence suggesting lower mortality among obese patients (i.e., obesity paradox). The scientific objectives of this proposal are to 1) investigate how adiposity-related factors at the molecular, individual, and neighborhood levels interplay to influence the RCC continuum—incidence, tumor aggressiveness, and survival—to reveal underlying mechanisms and uncover novel prevention avenues; 2) apply advanced causal inference methods to elucidate the true impact of body adiposity on RCC survival, the obesity paradox phenomenon. Aim 1 of this proposal will use causal mediation analysis with the UK Biobank (UKB) database to identify biological pathways through which excess body adiposity increases RCC incidence. Aim 2 will elucidate the true impact of body adiposity on RCC survival, examining life-course pre-diagnosis anthropometrics in the NIH-AARP Diet and Health Study (AARP) as well as pre-diagnosis adiposity-related biological pathways using the UKB. State-of-the-art causal inference methods will be implemented to ameliorate confounding, selection bias, and reverse causation that were inadequately addressed in previous studies. In addition, Aim 2 will explore how pre-diagnosis adiposity influences RCC aggressiveness, to test a potential biological hypothesis for the obesity paradox. Aim 3 will investigate how neighborhood socioeconomic characteristics and built environments that can promote weight gain (i.e., obesogenic environment) affect RCC incidence, aggressiveness, and survival. This aim will implement advanced multilevel methods using data from several large prospective cohort studies, including the AARP study, Nurses’ Health Study (1 and 2), and Health Professional Follow-up Study. The proposed research seeks to unravel the multilevel impacts of adiposity- related factors on the entire RCC continuum, providing insights for the underlying biological mechanisms and multilevel prevention efforts to reduce RCC incidence and improve outcomes. This research proposal is complemented by a career development plan that builds upon applicant’s background in medicine, environmental health, and cancer epidemiology. Specifically, this career development plan outlines new training in three areas: 1) molecular epidemiology in kidney cancer; 2) advanced causal inference methods; 3) multilevel approach for cancer prevention. The combined research and training plan will prepare the applicant for a successful independent research career identifying, evaluating, and implementing multilevel interventions to prevent cancer and promote overall health.