African American Specific Gene Panel Predictive of Poor Prostate Cancer Outcome

Abstract

Purpose: Most prostate cancer in African American men lacks the ETS (E26 transforming specific) family fusion event (ETS-). We aimed to establish clinically relevant biomarkers in African American men by studying ETS dependent gene expression patterns to identified race specific genes predictive of outcomes.

Materials and methods: Two multicenter cohorts of a total of 1,427 men were used for the discovery and validation (635 and 792 men, respectively) of race specific predictive biomarkers. We used false discovery rate adjusted q values to identify race and ETS dependent genes which were differentially expressed in African American men who experienced biochemical recurrence within 5 years. Principal component modeling along with survival analysis was done to assess the accuracy of the gene panel in predicting recurrence.

Results: We identified 3,047 genes which were differentially expressed based on ETS status. Of these genes 362 were differentially expressed in a race specific manner (false discovery rate 0.025 or less). A total of 81 genes were race specific and over expressed in African American men who experienced biochemical recurrence. The final gene panel included APOD, BCL6, EMP1, MYADM, SRGN and TIMP3. These genes were associated with 5-year biochemical recurrence (HR 1.97, 95% CI 1.27-3.06, p = 0.002) and they improved the predictive accuracy of clinicopathological variables only in African American men (60-month time dependent AUC 0.72).

Conclusions: In an effort to elucidate biological features associated with prostate cancer aggressiveness in African American men we identified ETS dependent biomarkers predicting early onset biochemical recurrence only in African American men. Thus, these ETS dependent biomarkers representing ideal candidates for biomarkers of aggressive disease in this patient population.

Keywords: African Americans; biomarkers; gene expression regulation; local; neoplasm recurrence; neoplastic; prostatic neoplasms; tumor.

Figure 1.

CONSORT diagram of gene discovery and validation protocol using GRID data. FDR, false discovery rate.

Figure 2.

Expression pattern of AAM and 6 outcome specific ETS dependent genes by race and ETS status. A, discovery data set. Single asterisk indicates p <0.025, double asterisks indicate p <0.01 and triple asterisks indicate p <0.001. B, validation data set. NS, not significant. Single asterisk indicates p <0.05, double asterisks indicate p <0.01 and triple asterisks indicate p <0.001.

Figure 3.

A, race stratified Kaplan-Meier curves of 5-year BCR risk using AAM specific gene panel. B, race stratified, time dependent area operating curve of Cox proportional hazard model using discovery data with AUC showing predictive ability of ETS dependent AAM specific genes for 5-year BCR at 60 months. Clinicopathologic only, Cox proportional hazard model with preoperative PSA, pathological Gleason score and age at diagnosis. Genes + clinicopathologic, Cox proportional hazard model with AAM specific genes and preoperative PSA, pathological Gleason score and age at diagnosis.