The genomic and proteomic landscape of Chinese familial prostate cancer reveals unique mutational signatures and targetable pathways

Prostate cancer in Chinese men presents distinct molecular features compared with Western populations, yet the genomic basis of familial cases remains poorly defined. Here, we present the first integrated genomic and proteomic profile of 108 Chinese familial prostate cancers versus matched sporadic controls. Familial tumors exhibited a substantially higher mutational burden, driven by FOXA1 in-frame deletions within the forkhead domain—an ethnic-specific hallmark—alongside a mismatch repair–deficient signature (COSMIC 15). Copy-number profiling revealed oncogene amplifications (MYC, PIK3CA) co-occurring with deletion of tumor suppressors (PTEN, RB1). Pathway-level analysis uncovered paradoxical AR signaling (high mutation load but reduced protein abundance), concordant RAS pathway hyperactivation, and NOTCH/Wnt mutational enrichment without proteomic change. Quantitative proteomics identified 303 differentially expressed proteins (DEPs), implicating energy metabolism reprogramming and RNA splicing dysregulation. These findings define lineage-specific vulnerabilities, providing a framework for precision risk assessment and targeted interventions in high-risk Chinese families.