Circulating Immune and Cancer Driver Gene Biomarkers Precede Prostate Cancer Diagnosis by over 10 yr.

BACKGROUND AND

OBJECTIVE

Prospective proteomic and proteogenomic studies may enhance the understanding of proteins associated with prostate cancer (PCa) development.

METHODS

In a case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC), baseline plasma samples from 982 incident PCa cases and 1573 subcohort participants were profiled using the SomaScan 7k platform (over 6000 proteins). Associations were estimated using Prentice-weighted Cox models. The coprimary end points were incident overall PCa and aggressive PCa (n = 290). Findings were evaluated in the Atherosclerosis Risk in Communities (ARIC) study and supported by Mendelian randomization (MR) and exome gene-burden analyses.

KEY FINDINGS AND LIMITATIONS: ACP3, FLT4, and KLK3 were associated with overall PCa risk (hazard ratio [HR] per 1 standard deviation [SD] increase were 1.20 [1.10-1.31], 1.26 [1.13-1.40], and 2.28 [1.96-2.65], respectively). Seven proteins were associated with aggressive PCa risk, with ANKRD1 consistently associated across multiple clinically relevant disease subtypes. Twelve proteins were associated with PCa diagnosed >15 yr after blood draw, including ANXA2, GZMK, and OSCAR. ACP3, ANXA2, APOC2, and KLK3 showed consistent associations in both EPIC and ARIC. Additionally, four proteins had support from MR analyses and eight from rare-variant burden tests. Circulating products of established PCa driver genes, including ERBB3, KRAS, and NRAS, were associated with future aggressive disease. Limitations include incomplete external replication and differences in end point availability across cohorts.

CONCLUSIONS AND CLINICAL IMPLICATIONS: Prospective plasma proteomic analyses identified circulating proteins associated with future PCa risk, including proteins related to immune, adhesion, angiogenesis, and PCa driver-gene pathways. These findings identify candidate protein risk factors for overall and clinically significant PCa, and warrant further validation and mechanistic evaluation.