Prospective validation and context-dependent effects of a prostate cancer germline variant at 8q24 in African ancestry men within the All of Us Research Program

Abstract

University of WashingtonAbstract Prospective validation and context-dependent effects of a prostate cancer germline variant at 8q24 in African ancestry men within the All of Us Research Program Ibrahim Duffus Chair of the Supervisory Committee: Burcu Darst Department of Epidemiology Background – Prostate cancer (PrCa) is one of the most frequently diagnosed cancers worldwide and remains a leading cause of cancer‑related death among men. PrCa burden is disproportionately spread across different races and ethnic groups, with Black and African American men experiencing the largest PrCa burden. PrCa is characterized by a complex interplay of biological and non-biological factors, and the genetic variant rs72725854 (A>T), located at the 8q24 chromosomal locus, has been established as the strongest genetic risk contributor for PrCa in men of African ancestry. rs72725854 (A>T) has been discovered to exert its effect on PrCa risk through a complex biological mechanism that activates nearby oncogenic elements, including the MYC oncogene, to drive PrCa tumorigenesis. Other PrCa risk factors could exert biological effects that modulate the mechanism's activity, thereby modifying the effect of rs72725854 (A>T). However, research thus far has not elucidated the mechanisms by which PrCa risk factors interact with rs72725854 (A>T). Understanding how rs72725854 (A>T) interacts with other PrCa risk factors could improve existing PrCa screening and prevention strategies and improve PrCa health-related outcomes in Black and African American individuals.Methods – This study employed a retrospective cohort design, consisting of a sample population of 23,413 Black or African American men enrolled in the All of Us Research Program (AoURP), to evaluate how biological and non-biological PrCa risk factors modify the effect of rs72725854 (A>T). Participant rs72725854 (A>T) genotypes were determined using short read whole genome sequencing, while exposures to PrCa risk factors, including neighborhood deprivation, obesity, alcohol consumption, and smoking habits were defined using electronic health record (EHR) diagnostic codes and participant survey responses. Participants were classified into incident or prevalent PrCa cases or controls based on EHR diagnostic codes. Associations between PrCa diagnosis and PrCa risk factors, as well as the multiplicative effect estimates of epistatic interactions between rs72725854 (A>T) and other 8q24 PrCa risk variants, and the gene–environment interactions between rs72725854 (A>T) and non‑biological factors, were evaluated using Cox proportional hazards models for incident cases and logistic regression models for prevalent cases, respectively. Additionally, additive interactions between rs72725854 and PrCa risk factors were evaluated using RERI‑based models. Results – rs72725854 (A>T) was significantly associated with PrCa risk in both the incident (n = 14,480) and prevalent cohorts (n = 20,933), with each copy of the risk allele conferring a 2.70-fold (HR = 2.72; 95% CI = 2.10–3.47; p < 0.001) and 1.95-fold (OR = 1.95; 95% CI = 1.65–2.32; p < 0.001) increase in PrCa risk, respectively. Out of 18 PrCa risk variants in the 8q24 locus, rs6983267 showed the most robust interaction with rs72725854 (A>T) on both the additive and multiplicative scale (OR = 2.22; 95% CI = 1.35–3.58; p = 0.001 and RERI = 1.28; 95% CI = 0.279–2.46; p = 0.03, respectively). Obesity and daily alcohol consumption were also observed to have significant interactions with rs72725854 (A>T), with obesity showing a significant interaction under additivity (RERI = 1.83; 95% CI = 0.337–3.52; p = 0.03) and daily alcohol consumption showing significant interaction under additivity (RERI = -1.99; 95% CI = -3.57 – -0.481; p = 0.01) and multiplicativity (HR = 0.46; 95% CI = 0.23–0.93; p = 0.03). Conclusion – The 8q24 rs72725854 (A>T) variant is a major PrCa risk factor among men of African ancestry, and its effect is modified by at least one other 8q24 variant, along with obesity and alcohol consumption. The mechanisms underlying these interactions warrant further research to improve our understanding of PrCa etiology and inform PrCa screening and prevention strategies for men of African Ancestry.