Abstract PR025: Mosaic loss of Y chromosome and risk of prostate cancer in two U.S. cohorts

Abstract Background: Mosaic loss of the Y chromosome (mLOY) in blood is the most common acquired somatic genomic event in aging men and has been implicated in cancer susceptibility. Experimental studies suggest loss of Y-chromosome gene expression, such as KDM5D, may contribute to tumor aggressiveness and poorer treatment response. However, epidemiologic evidence on mLOY in relation to prostate cancer incidence and clinical subtypes remains limited. Methods: We studied 6,081 cancer-free men from the prospective Health Professionals Follow-up Study (HPFS) and the Physicians’ Health Study (PHS) with genome-wide array data from pre-diagnostic blood samples. mLOY was inferred using MoChA by identifying phased B-allele frequency (BAF) deviations in the pseudoautosomal region (PAR) consistent with mosaic Y-chromosome loss, supported by reduced chromosome-Y log R ratio. The clonal fraction of mLOY was derived from BAF deviation. Cox proportional hazards models using age as the time scale estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall prostate cancer and by clinical subtype-specific prostate cancer (stage, Gleason score, PSA at diagnosis, and lethal disease defined by metastasis or prostate cancer-specific death), adjusting for body mass index, smoking, ancestry principal components, and array platform. Results: Median age at blood draw was 61 years (interquartile range: 53-68) and mLOY was detected in 635 men (10%), with clonal fraction ranging from 0.6% to 93.3% with a median of 21%. Over a median of 17 years of follow-up, 2,733 incident prostate cancer cases were documented, including 378 lethal cases. mLOY was associated with a higher risk of total (HR 1.23; 95% CI 1.08-1.39) and lethal prostate cancer (HR 1.42; 95% CI 1.07-1.90). Associations were stronger for cases with PSA ≥20 ng/mL at diagnosis (HR 1.66; 95% CI 1.08-2.55) than for those with PSA <10 ng/mL (HR 1.03; 95% CI 0.86-1.23). Elevated risks were also observed for late-onset disease (age ≥75 years: HR 1.36; 95% CI 1.11-1.67), but not early-onset disease (age <65 years: HR 0.94; 95% CI 0.63-1.40). A dose-response relationship was observed, with a higher mLOY clonal fraction associated with increased risk of total (per 5% higher: HR 1.03; 1.01-1.05) and lethal prostate cancer (HR 1.06; 95% CI 1.00-1.11). No statistically significant associations were observed for Gleason score or stage-specific diseases (p>0.05). Conclusions: In two prospective U.S. cohorts, blood-derived mLOY including higher clonal fraction was associated with increased prostate cancer risk many years in the future, particularly with lethal disease. These findings highlight the importance of acquired genomic alterations in aging hematopoietic cells in prostate cancer development and may inform risk stratification strategies for screening and early detection. Citation Format: Anqi Wang, Rebecca Kelly, Constance Turman, Anna Plym, Konrad Stopsack, Mitchell Machiela, Massimo Loda, Christopher Haiman, Philip Kantoff, Lorelei Mucci. Mosaic loss of Y chromosome and risk of prostate cancer in two U.S. cohorts [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr PR025.