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. Clin Cancer Res; 23(1); 81-87. ©2016 AACRSee related commentary by Yin et al., p. 6.

Figure 1. Expression levels of signature genes in Gleason score ≤6, Gleason score ≥8, and normal tissue

Expression levels of the 30 genes in the Gleason signature, in Gleason score ≤6 (Gl≤6, n=57) and Gleason score ≥8 (Gl≥8, n=106), and in all adjacent normal tissue (N, n=202). The genes are in order of importance in the model (reading left to right, then down). Differences with Bonferroni-corrected bootstrap p-value ≤0.05 are indicated: significant decreases (left to right) are indicated with a "−"; significant increases (left to right) are indicated with a "+". There are three main "patterns" of significant differences, indicated by the number of stars next to the gene name (0, 1 or 2). Genes with names without stars are similar between normal and Gl≤6 but differ in Gl≥8; genes with names with one star are significantly higher in Gl≤6 compared with normal and significantly lower in Gl≥8 when compared with both Gl≤6 and normal; and genes with names with two stars are significantly higher in Gl≤6 compared with normal and significantly lower in Gl≥8 compared with Gl≤6, but not significantly different between normal and Gl≥8.

Figure 2. Receiver operating characteristic (ROC) curves for the 30-gene signature

Curves are compared for the model including 3+4/4+3 status alone to the model including both 3+4/4+3 status and the 30-gene signature (p<0.0001).

Figure 3. Violin plot of the values of the 30-gene signature

Predicted probability of being high score (y-axis) among 4 categories of Gleason 7: Gleason 3+4 with indolent outcome, Gleason 3+4 with lethal outcome, Gleason 4+3 with indolent outcome, Gleason 4+3 with lethal outcome.