SATB1, genomic instability and Gleason grading constitute a novel risk score for prostate cancer

Abstract

Current prostate cancer risk classifications rely on clinicopathological parameters resulting in uncertainties for prognostication. To improve individual risk stratification, we examined the predictive value of selected proteins with respect to tumor heterogeneity and genomic instability. We assessed the degree of genomic instability in 50 radical prostatectomy specimens by DNA-Image-Cytometry and evaluated protein expression in related 199 tissue-microarray (TMA) cores. Immunohistochemical data of SATB1, SPIN1, TPM4, VIME and TBB5 were correlated with the degree of genomic instability, established clinical risk factors and overall survival. Genomic instability was associated with a GS ≥ 7 (p = 0.001) and worse overall survival (p = 0.008). A positive SATB1 expression was associated with a GS ≤ 6 (p = 0.040), genomic stability (p = 0.027), and was a predictor for increased overall survival (p = 0.023). High expression of SPIN1 was also associated with longer overall survival (p = 0.048) and lower preoperative PSA-values (p = 0.047). The combination of SATB1 expression, genomic instability, and GS lead to a novel Prostate Cancer Prediction Score (PCP-Score) which outperforms the current D'Amico et al. stratification for predicting overall survival. Low SATB1 expression, genomic instability and GS ≥ 7 were identified as markers for poor prognosis. Their combination overcomes current clinical risk stratification regimes.

Figure 1

Overall Survival stratified by (A) at least one tissue core with a high SATB1 expression per tumor (SATB1 positive), p = 0.02; (B) the number of tissue cores with a high SATB1 expression per tumor, p = 0.018; (C) and the SATB1 expression in one randomly chosen tissue core per tumor, p = 0.068; (D) TMA slide with SATB1 stained tissue cores (one TMA tissue core enlarged). P-values for the log-rank test.

Figure 2

Overall Survival stratified according to (A) D’Amico classification: low and intermediate risk (GS ≤ 7 and PSA ≤ 20 ng/ml and ≤ T2b) versus high risk (GS > 7 or PSA > 20 ng/ml or ≥ T3), p = 0.285 and (B) new PCP-Score: low risk (GS ≤ 6 and genomic stability and high SATB1 expression in at least one tissue core) versus high risk (GS ≥ 7 or genomic instability or low/negative SATB1 expression in all four obtained cores), p = 0.001; P-values for the log-rank test.

Figure 3

Age-adjusted hazard ratios of univariable cox regression analysis for all investigated parameters including combined parameters and the new Prostate Cancer Prediction Score (PCP). Positive = at least one tissue core with a high protein expression. SATB1 ≥ 2 cores =  ≥ 2 tissue cores with a high protein expression. SATB1 ≤ 1 core =  ≤ 1 tissue core with a high SATB1 expression. SATB1 random = high protein expression in only one randomly chosen tissue core. Red line: Hazard Ratio of new PCP-Score.