Unveiling cancer risk: an integrative approach to local environment and gene interplay

The local environment represents a group of variables associated directly or inversely to environmental pollution (such as air and noise pollution, the availability of greenspaces and water bodies, and street traffic volume). To characterize the effects of local environmental exposures on cancer risk represents an opportunity to develop primary prevention strategies. The principal objective of this doctoral research is to examine the impact of 12 environmental exposures on the likelihood of developing 17 cancer types, both as independent exposures and in conjunction with individual genetic predisposition. This study was conducted analyzing data from the UK Biobank prospective cohort using both traditional epidemiological techniques and an omics approach based on artificial intelligence (AI). Association analyses corroborated previously established associations and revealed previously unreported findings, such as the correlation between residing at a distance from the coast and the risk of prostate cancer (OR=1.02, 95%CI=1.01-1.03, P=7.01x10-7). Furthermore, an inverse association between air pollution and melanoma risk was demonstrated, with a particularly marked effect observed for particulate matter up to 2.5 µm (OR = 0.90, 95% CI = 0.86–0.93, P = 1.10 × 10⁻⁸). Mediation analyses suggest that the observed associations between the local environment and cancer risk could be explained by lifestyle. Moreover, no gene-environment interactions were identified, indicating that local environmental effects and genetic susceptibility are independent of one another. Finally, environmental exposures were integrated with non-modifiable risk factors (age, sex and genetic susceptibility) in an AI model to predict the risk of the most common forms of cancer. Despite the good discriminative abilities of the models (mean AUC = 0.94), the marginal effect of environmental exposures limits the applicability of these models. The findings of this study indicate that the local environment plays a significant role in the development of various forms of cancer, particularly lung cancer and skin melanoma. Additionally, the study identified new risk factors that require further investigation and confirmation in other cohorts. Furthermore, the independence between genetic susceptibility and local environmental exposures was underscored.