Association between the rs72725854(A>T) allele and prostate cancer in males of African ancestry in a US population-based database.

10504 Background: Black males have a 70% excess incidence of and two-fold higher mortality from prostate cancer (PCa) compared to White males in the US. The rs72725854(A>T) variant (‘T’ allele) is a common African ancestry-specific variant that is associated with PCa in large case-control studies in the US and Africa. We measured the association between the ‘T’ allele and PCa in a unique US population-based cohort. Methods: We conducted a retrospective time-to-event cohort study using the All of Us database (Duke IRB Pro00117610). We included males of African ancestry who met the following criteria: 1) were at least 35 years old at All of Us enrollment; 2) had undergone whole genome sequencing; 3) had linked electronic health record (EHR) data; 4) had no Systemized NOmenclature of MEDicine – Clinical Terms (SNOMED-CT) diagnosis of PCa prior to All of Us enrollment. PCa diagnoses were ascertained by the following EHR-based phenotyping algorithm: two PCa SNOMED-CT diagnosis codes plus evidence of PCa treatment with radical prostatectomy, radiotherapy or androgen deprivation therapy. The date of PCa diagnosis was defined as the latter of second diagnosis code date or first treatment date. Individuals were censored at last visit in the EHR if they did not meet the primary endpoint of PCa diagnosis. The association between each additional ‘T’ allele and time from All of Us enrollment to PCa diagnosis was measured using Cox regression methods, adjusting for the top 5 genetic principal components, age, and rare pathogenic variants (RPVs) in PCa predisposition genes ( ATM, BRCA1/2, HOXB13 X285K African-ancestry variant , and PALB2 ). Included RPVs had pathogenic/likely pathogenic designation in ClinVar with at least two stars. Results: Our study included 18,846 male participants of African ancestry, with 2,349 (12.5%) and 90 (0.5%) being heterozygous and homozygous for the ‘T’ allele, respectively. Median age at enrollment was 56.0 years (interquartile range 48.5 – 62.3). There were 91 cases of PCa during a median follow-up of 25.6 months (interquartile range 3.0 – 45.9). For each additional ‘T’ allele, there was a 3.4-fold increased hazard of PCa (HR 3.38; 95% CI 2.31 – 4.95; p 3.92x10 -10 ). Age (HR 1.09; 95% CI 1.06 – 1.11; p 2.74x10 -15 ) and RPVs in ATM (HR 7.54; 95% CI 1.84 – 30.90; p 5.03x10 -3 ) were also significantly associated with increased PCa diagnosis. BRCA2 RPVs (HR 4.94; 95% CI 0.68 – 35.68; p 0.112) and HOXB13 X285K (HR 2.61; 95% CI 0.36 – 19.02; p 0.343) were associated with PCa, but did not meet statistical significance. There were no BRCA1 or PALB2 RPVs among participants with PCa. Conclusions: In a large, US population-based study, we confirmed an association between the common rs72725854(A>T) variant and PCa diagnosis. This variant has a per-allele effect on PCa risk that is similar in magnitude to RPVs in PCa predisposition genes, and should be considered for inclusion in PCa genetic testing panels.