Abstract 4504: Developing a PTEN-ETS signature to improve molecular risk stratification in prostate cancer

Prostate cancer (PCa) is a heterogeneous disease and the development of a molecular classification is critical to distinguish lethal from indolent tumors and reduce overtreatment. Genomic alterations of the PTEN and ETS genes (e.g., ERG) are among the most common in PCa and there is a huge interest in exploiting these alterations for risk assessment. We have found that PTEN loss is associated with PCa death most strongly in patients whose tumors do not carry an ERG rearrangement, contradicting findings from mouse models. Despite technological advances have enabled extraordinary insight into PCa molecular alterations, our understanding of the interaction between PTEN and ETS genes during PCa progression remains very limited. Hence, we have analyzed a large collection of multi-omics datasets to characterize the molecular underpinnings of PTEN loss in the context of ETS-negative versus ETS-positive tumors and further investigate their role in driving PCa prognosis. First we have developed a classification approach for PCa stratification based on dichotomized gene expression of PTEN and ETS family members. We have then validated this approach using TCGA DNA copy number variation and rearrangement status information. Our results confirmed that transcriptome analysis can be used for detecting PTEN and ETS alterations, and that in the absence of ERG rearrangements, tumors with PTEN loss frequently overexpress alternative ETS genes. Next, we examined whether somatic mutation profiles might differ by PTEN/ETS status, providing an potential explanation for the lethal behavior of ERG-negative/PTEN-negative tumors. As expected SPOP mutation was found to be mutually exclusive with ERG expression, but it did not vary significantly by PTEN status. Most interestingly, TP53 mutation - the most frequently altered gene in lethal metastatic PCa - was significantly enriched among PTEN-negative tumors irrespective to ERG- status. Collectively these findings suggest that known prognosis-driving somatic mutations do not explain the aggressive behavior of ERG-negative/PTEN-negative tumors. Finally, we analyzed differential gene expression associated with PTEN loss in the presence or absence of ERG gene expression and identified the associated biological processes and signaling pathways. This analysis failed to confirm the correlation between ERG/ETV1 expression and higher androgen signaling output previously reported in murine models. Furthermore, our findings revealed that MYC targets and the genes involved in cell cycle progression are the most up-regulated by PTEN loss in ETS-negative tumors, while genes involved in cell differentiation, response to DNA damage, and TNF signaling are the most induced by PTEN loss in ERG-positive tumors. Overall, our analysis clarified some important aspects of the role of PTEN/ETS network in PCa progression, suggesting a number of promising targets for the development of novel therapeutic interventions. Citation Format: Luigi Marchionni, Tamara L. Lotan. Developing a PTEN-ETS signature to improve molecular risk stratification in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4504.