Abstract B69: Aggressiveness and tumor biology in prostate cancer patients with and without biochemical recurrence
Authors: Acosta Natalia , Zabaleta Jovanny , Varela Rodolfo , Mesa Jorge , Serrano Silvia , Garay Jone , Baddoo Melody , Nataly Cruz , Combita Alba Lucía , Sanabria-Salas María Carolina 
Published: February 2019

Background: Prediction of biochemical recurrence (BCR) using standard measures to assign risk classification in prostate cancer (PCa) patients at diagnosis is not precise. While in some patients BCR may happen sooner than expected in others, it may take several years before it appears. It is then necessary to devise better tools to predict accurately BCR. Our goal was to identify differentially expressed genes (DEGs) in cases with and without BCR within the risk groups determined by D'Amico (defined by the clinical stage, initial PSA, and Gleason stage in biopsy).

Methods: We ran RNA-seq analysis in 52 Hispanic PCa patients with early BCR (within 5 years after the surgery) and 57 with no BCR in the same period of time. The cases were classified as high, intermediate, or low according to the D'Amico classification. Analyses were done using the DESeq2 package. Genes with p value adjusted by False Discovery Rate (padj) less than 0.05 and fold change (FC) &gt; 2 were considered statistically significant. Pathway analysis was performed in MetaCore.

Results: We found 4,281 DEGs (padj &lt; 0.05) associated with tumor tissues in the BCR cases (7 of those with a FC &gt; 2). In contrast, 4,647 DEGs were associated with tumor tissues in cases without BCR (16 with FC &gt; 2). Of these genes, nine (CHRM3, CLDN8, ERG, GDF15, LUZP2, OR51E1, PTPRT, TRGC1, TPO) were exclusively found in cases without BCR, and one, ONECUT2, was exclusive for tissues with BCR. All these genes, except TRGC1, have been associated before with PCa: the Cholinergic Receptor Muscarinic 3 (CHRM3) and the Olfactory Receptor Family 51 Subfamily E Member 1 (OR51E1) have a growth-promoting role; Claudin 8 (CLDN8) is transcriptionally activated by the androgen receptor to promote progression of PCa; ETS Trancription Factor (ERG) participates in chromosomal translocation in PCa and is involved in cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis; Growth Differentiation Factor 15 (GDF15) was reported to be part of a circulating tumor cell profile in castration-resistant PCa with high levels associated with poor survival; Leucine Zipper Protein 2 (LUZP2) seems to contribute to enzalutamide resistance in castration-resistant PCa; Protein Tyrosine Phosphatase Receptor Type T (PTPRT) was recently found overexpressed in localized PCa; Thyroid Peroxidase (TPO) promotes resistance to cell death and to chemotherapy in PCa; and ONECUT2 has been associated with different types of cancer and recently with prostate cancer. Pathway analysis of DEGs identified IL-6 signaling pathway via MEK/ERK and PI3K/AKT cascades; PPAR pathway activation (which involves transcription factors belonging to the nuclear hormone receptor superfamily and activated by fatty acids); and Adenosine A2B receptor signaling, which indirectly activates c-Myc, Cyclin D1, PI3K/AKT, and IL-6 in patients with BCR. On the other hand, IL-15 signaling via JAK-STAT cascade, WNT signaling pathway, G-protein signaling, apoptosis, and survival through NGF/TrkA PI3K-mediating signaling and mTORC2 downstream signaling pathways were identified in the group without BCR. These differences show that DEGs in both groups, even though implicated in processes related with tumor development, are involved in specific pathways that can be associated with the grade of aggressiveness of the tumors, and also, under specific circumstances, lead to BCR. In addition, we found that DEGs can separate BCR from no BCR cases within each risk group, suggesting that a genomic signature with DEGs is a better predictor of BCR than the clinically assigned risk groups.

Conclusions: Tumor biology and signaling pathways activated in cases with BCR are different from those in cases without BCR, showing that aggressiveness of tumors can be found at the moment of surgery and that biomarkers of prognosis can be identified at this point.

Citation Format: Natalia Acosta, Jovanny Zabaleta, Rodolfo Varela, Jorge Mesa, Silvia Serrano, Jone Garay, Melody Baddoo, Cruz Nataly, Alba Lucía Combita, María Carolina Sanabria-Salas. Aggressiveness and tumor biology in prostate cancer patients with and without biochemical recurrence [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B69.