Abstract B67: Identifying obesity-linked gene expression changes in prostate cancer
Authors: Ebot Ericka M. , Gerke Travis , Tyekucheva Svitlana , Labbé David P. , Zadra Giorgia , Kelly Rachel S. , Bowden Michaela , Rider Jennifer R. , Wilson M Kathryn , Martin Neil E. , Brown Myles , Heiden Matthew G. Vander , Giovannucci Edward L. , Loda Massimo , Mucci Lorelei A. 
Published: May 2016

Background: Obese men are at higher risk of advanced prostate cancer and have higher rates of cancer-specific mortality after diagnosis. The biological mechanisms explaining this association are unknown. Using mRNA expression profiles of tissue from prostate cancer patients, we aimed to identify pathways that are differentially altered among overweight/obese men compared to healthy weight men.

Methods: The study includes men with prostate cancer in the Health Professionals Follow-up Study and the Physicians' Health Study, for whom archival tissue and long-term follow-up is available. Whole genome mRNA expression profiling was performed on tumor (N=402) and adjacent normal (N=200) tissue using the Affymetrix GeneChip Human Gene 1.0 ST Array. Body mass index (BMI) was taken from questionnaires before diagnosis. Among 402 men in the study, 113 lethal events (metastasis or death) were recorded. We identified top Gene Ontology biological processes differentially expressed by obesity status using Gene Set Enrichment Analysis (GSEA). Pathway scores were computed for each tumor by averaging the normalized signal intensities of all member genes. Odds ratios for lethal disease were estimated using logistic regression.

Results: 48% of men were healthy weight (BMI 18.5 to &lt;25 kg/m2), 31% were overweight (BMI 25 to &lt;27.5 kg/m2), and 21% were very overweight/obese (BMI ≥27.5 kg/m2) at diagnosis. GSEA identified 15 gene sets enriched in the tumor tissue of very overweight/obese vs healthy weight men (FDR &lt; 0.25). Interestingly, 9 of the 15 gene sets were epigenetic processes related to chromatin remodeling and RNA processing. Other biological processes identified were macromolecular complex disassembly, Golgi vesicle transport, and ribonucleotide metabolic process. No pathways reached FDR &lt; 0.25 in adjacent normal tissue indicating these results are tumor-specific.

To look further into the role of chromatin remodeling, we calculated a pathway score based on 35 chromatin-related leading edge genes from the obesity GSEA. As expected, the score was significantly associated with BMI. In addition, the score was positively associated with pathologic stage and Gleason grade. After adjustment for age and year at diagnosis, the score was associated with lethal progression, with an odds ratio of 6.78 (95% CI: 3.42, 14.16) for lethal outcome comparing extreme quartiles. After further adjusting for stage and Gleason grade the odds ratio decreased slightly but remained significant. In a mediation analysis, we found that 36% of the BMI effect on lethal outcome was mediated by the score.

Conclusion: Genes involved in chromatin regulation were enriched in tumor tissue of obese men. Tumors with high expression of these genes were found to have worse clinical characteristics and poorer outcomes. Our findings support a role for epigenetic regulation in the obesity-lethal prostate cancer relationship.

Citation Format: Ericka M. Ebot, Travis Gerke, Svitlana Tyekucheva, David P. Labbé, Giorgia Zadra, Rachel S. Kelly, Michaela Bowden, Jennifer R. Rider, M Kathryn Wilson, Neil E. Martin, Myles Brown, Matthew G. Vander Heiden, Edward L. Giovannucci, Massimo Loda, Lorelei A. Mucci. Identifying obesity-linked gene expression changes in 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 B67.