Mosaic loss of the Y chromosome in leukocytes is associated with increased incidence of non-aggressive prostate cancer in 278,998 cancer-free males

Background: Mosaic loss of the Y chromosome (mLOY), a type of clonal hematopoiesis, is the most frequently detected chromosomal alteration in the leukocytes of aging males. Prostate cancer (PCa) increases exponentially in aging males and previous studies have shown a positive association between genetic risk of mLOY and PCa diagnosis. Confirmation of this association in population-based studies is needed to determine if mLOY could be an informative biomarker for PCa risk. Methods: To evaluate the potential association between mLOY and prostate cancer risk, we detected mLOY using the MoChA algorithm on existing high-density genotyping array data from blood-derived DNA of 278,998 cancer-free males across six prospective cohorts: UK Biobank (UKBB, N=210,103); Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, N=26,275); Health Professionals' Follow-Up Study (HPFS, N=4,933); Physicians' Health Study (PHS, N=1,148); Multiethnic Cohort (MEC, N=24,370); and Cancer Prevention Study II (CPSII, N=12,169). Cox proportional hazards models with age as a timescale estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association of mLOY on prostate cancer incidence adjusted for body mass index, smoking status, genotyping array, and the top 10 genetic principal components. Association tests were performed in each cohort and then meta-analyzed. Results: The average mLOY detection and PCa diagnosis across cohorts were 23.4% and 17.9%, respectively. Fixed effects meta-analysis of the adjusted HRs identified a positive association of mLOY with overall PCa risk (HR=1.09, CI 1.05, 1.13; P-Value ( P )=2.25 x 10 -6 ). mLOY was associated with a Gleason score ≤6 at diagnosis (HR=1.13, 95% CI 1.04, 1.23; P =0.0029), a greater hazard of non-aggressive PCa diagnosis (HR=1.15, 95% CI 1.05, 1.26; P =0.0022), and PSA <10ng/mL at diagnosis (HR=1.11, 95% CI 1.02, 1.22; P =0.015). We did not observe evidence for mLOY associations with Gleason score ≥8, aggressive PCa or metastasis at diagnosis. We confirmed germline genetic risk of mLOY was positively associated with PCa incidence in participants with genetic similarity to European reference populations (HR=1.02 per 1 SD mLOY PRS, 95% CI 1.00, 1.03; P =0.0083), there was less evidence in participants similar to African reference populations (HR=1.01 per 1 SD mLOY PRS, 95% CI 0.94, 1.08; P =0.769). Conclusion: Our investigation of the relationship between mLOY and PCa diagnosis provides evidence for an association between mLOY detected in the blood and increased risk of non-aggressive PCa, suggesting mLOY could have utility in PCa risk stratification.