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This study examined gene expression profiles of prostate tissue to identify biological processes differentially expressed by obesity status and lethal prostate cancer.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Gene expression profiling was performed on tumor (n = 402) and adjacent normal (n = 200) prostate tissue from participants in 2 prospective cohorts who had been diagnosed with prostate cancer from 1982 to 2005. Body mass index (BMI) was calculated from the questionnaire immediately preceding cancer diagnosis. Men were followed for metastases or prostate cancer\u2013specific death (lethal disease) through 2011. Gene Ontology biological processes differentially expressed by BMI were identified using gene set enrichment analysis. Pathway scores were computed by averaging the signal intensities of member genes. Odds ratios (ORs) for lethal prostate cancer were estimated with logistic regression.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Among 402 men, 48% were healthy weight, 31% were overweight, and 21% were very overweight\/obese. Fifteen gene sets were enriched in tumor tissue, but not normal tissue, of very overweight\/obese men versus healthy\u2010weight men; 5 of these were related to chromatin modification and remodeling (false\u2010discovery rate &lt; 0.25). Patients with high tumor expression of chromatin\u2010related genes had worse clinical characteristics (Gleason grade &gt; 7, 41% vs 17%; <jats:italic>P<\/jats:italic> = 2 \u00d7 10<jats:sup>\u20134<\/jats:sup>) and an increased risk of lethal disease that was independent of grade and stage (OR, 5.26; 95% confidence interval, 2.37\u201012.25).<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>This study improves our understanding of the biology of aggressive prostate cancer and identifies a potential mechanistic link between obesity and prostate cancer death that warrants further study. <jats:bold><jats:italic>Cancer<\/jats:italic> 2017;123:4130\u20134138.<\/jats:bold> \u00a9 <jats:italic>2017 American Cancer Society<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.30831","type":"journal-article","created":{"date-parts":[[2017,7,12]],"date-time":"2017-07-12T13:24:43Z","timestamp":1499865883000},"page":"4130-4138","source":"Crossref","is-referenced-by-count":17,"title":["Gene expression profiling of prostate tissue identifies chromatin regulation as a potential link between obesity and lethal prostate cancer"],"prefix":"10.1002","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7144-693X","authenticated-orcid":false,"given":"Ericka M.","family":"Ebot","sequence":"first","affiliation":[{"name":"Department of Epidemiology Harvard T. 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