Prognostic Utility of a New mRNA Expression Signature of Gleason Score

Abstract

Purpose: Gleason score strongly predicts prostate cancer mortality; however, scoring varies among pathologists, and many men are diagnosed with intermediate-risk Gleason score 7. We previously developed a 157-gene signature for Gleason score using a limited gene panel. Using a new whole-transcriptome expression dataset, we verified the previous signature's performance and developed a new Gleason signature to improve lethal outcome prediction among men with Gleason score 7.Experimental Design: We generated mRNA expression data from prostate tumor tissue from men in the Physicians' Health Study and Health Professionals Follow-Up Study (N = 404) using the Affymetrix Human Gene 1.0 ST microarray. The Prediction Analysis for Microarrays method was used to develop a signature to distinguish high (>= 8) versus low (<= 6) Gleason score. We evaluated the signature's ability to improve prediction of lethality among men with Gleason score 7, adjusting for 3+4/4+3 status, by quantifying the area under the receiver operating characteristic (ROC) curve (AUC). Results: We identified a 30-gene signature that best distinguished Gleason score <= 6 from >= 8. The AUC to predict lethal disease among Gleason score 7 men was 0.76 [95% confidence interval (CI), 0.67-0.84] compared with 0.68 (95% CI, 0.59-0.76) using 3 + 4/4 + 3 status alone (P = 0.0001). This signature was a nonsignificant (P = 0.09) improvement over our previous signature (AUC = 0.72). Conclusions: Our new 30-gene signature improved prediction of lethality among men with Gleason score 7. This signature can potentially become a useful prognostic tool for physicians to improve treatment decision making.