Gene expression profiling of human prostate tumors identifies chromatin remodeling as a molecular link between obesity and lethal prostate cancer

Obese men are at higher risk of developing advanced prostate cancer and have higher rates of cancer-specific mortality. However, the biological mechanisms explaining these associations are unknown. Using gene expression data, we aimed to identify molecular alterations in prostate cancer tissue associated with obesity. Gene Set Enrichment Analysis identified fifteen gene sets up-regulated in the tumor tissue of obese prostate cancer patients (N=84) compared to healthy weight patients (N=192), five of which were related to chromatin remodeling. These gene sets were not identified in an analysis of adjacent normal tissue. Patients with tumors with high expression of chromatin remodeling genes had worse clinical characteristics (Gleason grade >7, 41% versus 17%, p-trend = 3.21 x 10-4) and poorer prostate cancer-specific survival independent of Gleason grade (lethal outcome, OR = 5.01, 95% CI = 2.31 to 11.38). Mediation analysis further supported a role for chromatin remodeling in the obesity-lethal prostate cancer relationship. Gene expression profiling was performed on 602 prostate tissue samples (402 tumor and 200 normal) from the Health Professionals Follow-up Study and Physicians' Health Study Prostate Tumor Cohort. This study includes analysis of 400 samples in GSE62872.