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Background: Genome-wide association studies have identified hundreds of susceptibility loci for various cancer sites including prostate cancer. Several of the risk loci have demonstrated pleiotropic effects with multiple cancers, suggesting shared biological pathways in carcinogenesis. In the present study, we systematically investigated the effects of other cancer-associated variants on prostate cancer risk. Methods: We examined 196 genetic risk variants identified for 18 cancer and cancer-related traits in a total of 28,135 prostate cancer cases and 37,218 controls. This large meta-analysis of multiethnic samples was assembled from three consortia: Population Architecture using Genetics and Epidemiology (PAGE), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) and Breast and Prostate Cancer Cohort Consortium (BPC3). Study- and ethnic-specific logistic regressions results were combined through fixed-effect meta-analysis to evaluate the association between each variant and prostate cancer risk, applying a Bonferroni-corrected significance threshold of 2.6×10-4. We also assessed the cumulative effect of other cancer risk variants on prostate cancer susceptibility via risk score analysis. Results: Three variants, RTEL rs6010620, TERT rs2853676 and HLA rs6457327, demonstrated statistically significant associations with prostate cancer risk after correcting for multiple comparisons. Originally reported as a follicular lymphoma risk variant, rs6457327 was associated with prostate cancer at the genome-wide significant level (meta-analysis OR=0.93, 95% CI: 0.91-0.96; p=4.5×10-8). The cumulative genetic risk score for risk variants of other cancers demonstrated a significant effect on prostate cancer risk (p=0.021). Conclusions: This systematic pleiotropy analysis identified HLA as a novel susceptibility locus for prostate cancer in a large multiethnic population. The genetic variant with pleiotropic effects on both follicular lymphoma and prostate cancer provides evidence for shared etiologic mechanisms between prostate cancer and other cancer sites. Citation Format: Ying Han, Shelly-Ann Love, William S. Bush, Daniele Campa, Anne M. Butler, Logan Dumitrescu, Konstantinos Tsilidis, Iona Cheng, Lynne R. Wilkens, Jay H. Fowke, Jose Luis Ambite, Steve Buyske, S. Lani Park, The PRACTICAL Consortium, The BPC3 Consortium, Christopher A. Haiman, Loic Le Marchand, Lucia A. Hindorff, Federico Canzian, Fredrick R. Schumacher. Pleiotropy analysis identifies a novel prostate cancer variant at 6p21.33: The PAGE, PRACTICAL, and BPC3 Consortia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5064. doi:10.1158/1538-7445.AM2014-5064