Abstract 1555: A gene signature associated with PTEN activation defines good outcomes in intermediate-risk prostate cancer cases
Authors: Chee Wee Ong, Pamela Maxwell, Muhammad A. Alvi, Stephen McQuaid, Ian G. Mills, Manuel Salto-Tellez, David J. Waugh
Journal: Cancer Research (2018)

Abstract Background: Accurate identification of Gleason score (GS) 3+4 prostate cancer patients with low risk of disease progression is an unmet challenge in treatment decision making. We investigated the potential of using integrative genomic profiling to improve stratification of GS 3+4 prostate cancer patients to aid decision making. Methods: High-throughput gene expression, methylation and mutational analysis were performed on a subset of 28 GS 3+4 cases selected from a cohort (N = 69) of intermediate risk prostate cancer cases. Preselection was based on immunohistochemistry (IHC) expression of 6 major drivers (PTEN, MYC, RB1, TP53, AURKA and AR) of aggressive disease in prostate cancer. Fuzzy clustering and unsupervised hierarchical clustering were utilized to determine molecular subgroups. Genes with high expression differences between subgroups were identified through group difference statistics. A prognostic index based on Cox proportional hazard model was generated for individual and combinations of differentially expressed genes and was tested in GS 3+4 cases (total N = 215, median follow-up = 65.8 months) extracted from 3 prostate cancer datasets available at Gene Expression Omnibus (GSE21032, GSE16560 and GSE40272). Hazard risk (HR) and 95% confidence interval (CI) of association with outcomes (recurrence and overall survival) were analyzed using Cox modelling and log-rank analysis. Results: We found that GS 3+4 prostate cancer cases could be classified as "complex" (differential expression of more than one driver) or "simple" (differential expression of only one) based on IHC analysis. Focusing on the "simple" cases, gene expression and methylation PTEN expression were tightly correlated and not observed in other drivers (R = 0.41, P = 0.03). Group difference statistics showed 35 genes were highly expressed in PTEN-high subgroup and were evaluated individually and in combination for prognostic value in 3 independent cohorts. The prognostic potential of the combinatorial signature was observed in all 3 cohorts: GSE21032 (HR: 6.95, 95% CI: 2.73-17.54, P &amp;lt; 0.001), GSE40272 (HR: 6.40, 95% CI: 2.28-17.96, P &amp;lt; 0.001) and GSE16560 (HR: 1.77, 95% CI, 1.29-2.41; P = 0.003) datasets. Individual gene-by-gene analysis showed that 4 genes (ACTA2, ACTG2, MYH11 and TPM2) were prognostic (all P &amp;lt; 0.05) in all 3 cohorts. Compared to the combination of 35 genes (AUC = 0.728), the prognostic potential of combining these 4 genes was still of significant value (AUC = 0.689). Conclusion: This study shows that by using IHC as an upfront stratifier of intermediate risk prostate cancers, it is possible to identify, through subsequent differential gene expression profiling, a geneset with prognostic power across multiple cohorts. This strategy has not been used previously and the signature, subject to further validation, has the potential to impact on treatment decisions in GS 3+4 prostate cancer patients. Citation Format: Chee Wee Ong, Pamela Maxwell, Muhammad A. Alvi, Stephen McQuaid, Ian G. Mills, Manuel Salto-Tellez, David J. Waugh. A gene signature associated with PTEN activation defines good outcomes in intermediate-risk prostate cancer cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1555.