Abstract 4686: 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 Kathryn M. , Martin Neil E. , Brown Myles , Vander Heiden Matthew G. , Giovannucci Edward L. , Loda Massimo , Mucci Lorelei A. 
Published: August 2015

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 aim to identify pathways that are differentially altered in tumor and adjacent normal tissue of overweight/obese men compared to healthy weight men.

Methods: The study includes men with prostate cancer in the Health Professionals Follow-up Study (HPFS) and the Physicians’ Health Study (PHS), for whom archival tissue and long-term follow-up is available. Whole genome mRNA expression profiling was performed on tumor tissue (N = 402) and adjacent normal tissue (N = 200) using the Affymetrix 1.0 ST array. Body mass index (BMI) was taken from questionnaires before diagnosis. Among 402 men in the study, 111 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). Single sample GSEA was used to generate pathway scores. 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. Results from an analysis on the adjacent normal tissue indicate that 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 PSA at diagnosis, 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 5.11 (95% CI: 2.60, 10.52) for lethal outcome comparing extreme quartiles. After further adjusting for pathologic stage and Gleason grade the odds ratio decreased slightly but remained significant. In a mediation analysis, we found that 57% 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 to be associated with worse 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, Kathryn M. 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 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4686. doi:10.1158/1538-7445.AM2015-4686