Abstract A1-64: Molecular and clinical characterization of 1,577 primary prostate cancer tumors reveals novel clinical and biological insights into its subtypes
Authors: Alshalalfa Mohammed , Tomlins Scott A. , Erho Nicholas , Yousefi Kasra , Zhao Shuang , Den Robert B. , Dicker Adam P. , Trock Bruce , DeMarzo Angelo , Schaeffer Edward M. , Ross Ashley , Klein Eric A. , Magi-Galluzzi Cristina , Karnes Jeffery R. , Jenkins Robert B , Davicioni Elai , Feng Felix 
Published: November 2015

Background: Prostate cancer molecular subtypes based on ETS gene fusions and SPINK1 were originally identified through distinct gene expression profiles. Such molecular subtypes may have utility in disease stratification and clonality assessment, complementing available purely prognostic tests. Hence, we determined the analytical validity of molecular subtyping and explored clinical associations using global gene expression profiles in a large cohort of PCa.

Methods: We analyzed 1,577 patient Affymetrix Human Exon 1.0ST GeneChip expression profiles from 8 radical prostatectomy (RP) cohorts; 5 of them generated as part of the Decipher® platform for the Decipher® discovery or validation. Multi-feature random forest classifiers and outlier analysis were used to define microarray-based molecular subtypes and characterize clinical associations.

Results: A random forest (RF) classifier (m-ERG) was trained and validated to predict ERG fusion status using separate subsets of a single-institution RP cohort (total n=407) with known ERG rearrangement status defined by FISH, achieving &gt;95% sensitivity and specificity in the validation subset. The model was then applied to 7 independent RP cohorts to predict ERG rearrangement status. Less frequent rearrangements involving other ETS genes (ETV1, ETV4, ETV5, FLI1) or SPINK1 over-expression were predicted based on gene expression outlier analysis. Across cohorts, 45%, 9% 8% and 38% of PCa were classified as ERG+, ERG—ETS+, ERG—SPINK+, and Triple Negative (ERG—/ETS—/SPINK1—), respectively. Global gene expression analysis shows that the four subtypes could be collapsed into three entities (ERG+, ERG—ETS+ and SPINK+/Triple Negative) based on expression patterns and clinical characteristics similarity. Based on multivariable analysis, ERG+ is significantly associated with lower pre-PSA (p&lt;0.001), lower Gleason score (p&lt;0.001), the presence of extraprostatic extension (p&lt;0.001) and European Americans (p&lt;0.001), but not associated with outcome. ERG—ETS+ is significantly associated with SVI (p=0.01) and ERG—SPINK+ is enriched in African Americans (p&lt;0.001).

Conclusions: The Decipher® platform can accurately determine ERG rearrangement status and PCa molecular subtypes. Inclusion of molecular subtyping, such as m-ERG status, may enable additional precision medicine opportunities in prognostic tests and provides insights into the development of novel therapeutic approaches.

Citation Format: Mohammed Alshalalfa, Scott A. Tomlins, Nicholas Erho, Kasra Yousefi, Shuang Zhao, Robert B. Den, Adam P. Dicker, Bruce Trock, Angelo DeMarzo, Edward M. Schaeffer, Ashley Ross, Eric A. Klein, Cristina Magi-Galluzzi, Jeffery R. Karnes, Robert B Jenkins, Elai Davicioni, Felix Feng. Molecular and clinical characterization of 1,577 primary prostate cancer tumors reveals novel clinical and biological insights into its subtypes. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-64.