Abstract A25: Tumor metabolism as a driver of lethal prostate cancer
Authors: Kelly Rachel S. , Sinnott Jennifer A. , Rider Jennifer R. , Ebot Ericka , Gerke Travis , Penney Kathryn L. , Bowden Michaela , Pettersson Andreas , Loda Massimo , Stampfer Meir , Kantoff Philip , Martin Neil E. , Giovannucci Edward L. , Tyekucheva Svitlana , Heiden Matthew Vander , Mucci Lorelei A. 
Published: May 2016

Abstract
Background: Recent evidence suggests that dysregulation of tumor metabolism is a key feature in the progression of normal prostate epithelium to cancer, and that it may also reflect disease aggressiveness and metastatic potential. Identifying and understanding the biologic differences between lethal and non-lethal prostate cancer tumors and illuminating the key mechanisms underlying the progression to a lethal phenotype is critical to the study of this common malignancy.
Methods: mRNA was extracted from the tumors of 404 participants of the Health Professionals Follow-up Study and the Physicians' Health Study diagnosed with incident prostate cancer (113 lethal (prostate cancer death or metastases) and 291 non-lethal), and from adjacent histologically normal tissue available for 202 of these cases. mRNA expression was analyzed for 401 metabolic genes encoding enzymes involved in several metabolic pathways: Fatty Acid metabolism, Glycolysis/Gluconeogenesis, Oxidative Phosphorylation, Pentose Phosphate, Purine metabolism, Pyrimidine metabolism and the TCA cycle. Gene and pathway-level differences in expression between lethal and non-lethal tumors were assessed, and the findings compared to the expression patterns in adjacent normal tissue. Potential confounders and effect modifiers including cohort, age, year of diagnosis, BMI at diagnosis, subtype heterogeneity, clinical tumor stage, and Gleason grade were explored and multiple testing was accounted for.
Results: Two thirds (93/123) of the genes significantly (p&lt;0.05) associated with lethality were overexpressed in the lethal compared to non-lethal tumors, including POLR2K (p=5.8x10-9), RRM2 (p=7.7x10-9), ATP6V1A (p=7.8x10-8) and POLE2 (p=7.4x10-7). ALDH2 (p=4.7x10-8) and PDE4DE (p=7.1x10-8) were the top genes that were overexpressed in the non-lethal tumors. On a pathway level Glycolysis/Gluconeogenesis (p=8.7x10-12), Purine metabolism (p=5.6x10-9), Pyrimidine metabolism (p=1.3x10-7) and Oxidative Phosphorylation (p=5.3x10-6) were the metabolic pathways most strongly associated with lethality. Only the TCA cycle displayed no evidence of an association. There was no difference in expression of the pathways in normal adjacent tissue among the lethal compared to non-lethal cases, however there was strong evidence of dysregulation of all pathways in the normal compared to tumor tissue. These results were robust to potential confounders including Gleason grade.
Conclusions: In this large prostate cancer study, we demonstrate alterations in key metabolic pathways within the prostate during carcinogenesis, and offer evidence that these changes differ in lethal compared to non-lethal tumors. We additionally identify novel associations with the expression of certain metabolic genes. There was no evidence for a strong role of the tumor microenvironment in this study. Our results were robust to confounding and independent of Gleason grade. A better comprehension of the dysregulation in the genes and pathways involved in lethality may offer novel therapeutic targets for the treatment of prostate cancer.
Citation Format: Rachel S. Kelly, Jennifer A. Sinnott, Jennifer R. Rider, Ericka Ebot, Travis Gerke, Kathryn L. Penney, Michaela Bowden, Andreas Pettersson, Massimo Loda, Meir Stampfer, Philip Kantoff, Neil E. Martin, Edward L. Giovannucci, Svitlana Tyekucheva, Matthew Vander Heiden, Lorelei A. Mucci. Tumor metabolism as a driver of lethal prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A25.