Molecular stratification of SPOP-mutant prostate cancer demonstrates Wnt signaling and replication stress signatures in diverse patient populations.

Speckle-type POZ protein (SPOP) mutations define a molecular subtype of prostate cancer, but their genomic and transcriptional features across racially diverse populations remain incompletely resolved. We integrated tumor genomic profiles from 273 patients, including 40 SPOP-mutant tumors, with RNA sequencing from 102 cases to characterize SPOP-associated alterations across disease stage and self-reported race. SPOP-mutant tumors showed significant enrichment of APC and other recurrent co-alterations, supporting Wnt pathway dysregulation as a defining genomic feature. Transcriptomic analysis revealed enhanced proliferative, metabolic, and biosynthetic programs accompanied by suppression of extracellular matrix, structural, and differentiation-associated pathways. Race-stratified analyses identified a conserved repression of structural programs but divergent transcriptional activation states: African American SPOP-mutant tumors preferentially exhibited inflammatory, hypoxic, and epithelial plasticity programs, whereas Caucasian tumors showed stronger MYC, oxidative phosphorylation, translational, and androgen-response signatures. These findings define SPOP-mutant prostate cancer as a molecularly distinct, context-dependent disease subtype with potentially heterogeneous, clinically relevant therapeutic vulnerabilities across patient populations.