The local environment and germline genetic variation predict cancer risk in the UK Biobank prospective cohort

Background: There is a growing body of evidence on the effect of the local environment exposure on cancer susceptibility. Nonetheless, several of the associations remain controversial. Moreover, our understanding of the possible interaction between the local environment and the genetic variability is still very limited. Objective: The aim of this study was to clarify the role of the local environment and its possible interplay with genetics on common cancers development.Methods: Using the UK Biobank (UKBB) prospective cohort, we selected 12 local environment exposures: nitrogen oxides, nitrogen dioxides, particulate matter (10 and 2.5 mu m), noise pollution, urban traffic, living distance from the coast, percentage of greenspace, natural environment, water, and domestic garden within 1000 m from the residential coordinates of each participant. All these exposures were tested for association with 17 different types of cancer for a total of 53,270 cases and 302,645 controls. Additionally, a polygenic score (PGS) was computed for each cancer, to test possible gene-environment interactions. Finally, mediation analyses were carried out.Results: Thirty-six statistically significant associations considering multiple testing (p < 2.19 x 10(-4)) were observed. Among the novel associations we observed that individuals living farther from the coast had a higher risk of developing prostate cancer (OR = 1.13, CI95% = 1.06-1.20, P = 1.98 x 10(-4)). This association was partially mediated by physical activity (indirect effect (IE) =-8.48 x 10(-7)) and the time spent outdoor (IE = 9.07 x 10(-6)). All PGSs showed statistically significant associations. Finally, genome-environment interaction analysis showed that local environment and genetic variability affect cancer risk independently.Discussion: Living close to the coast and air pollution were associated with a decreased risk of prostate cancer and skin melanoma, respectively. These findings from the UKBB support the role of the local environment on cancer development, which is independent from genetics and may be mediated by several lifestyle factors.