Ericka M Ebot1, Travis Gerke1,2, David P Labbé3,4, Jennifer A Sinnott1,5, Giorgia Zadra3,6, Jennifer R Rider1,7, Svitlana Tyekucheva8,9, Kathryn M Wilson1,10, Rachel S Kelly10, Irene M Shui1, Massimo Loda3,6, Philip W Kantoff11, Stephen Finn12, Matthew G Vander Heiden3,13, Myles Brown3,4, Edward L Giovannucci1,10,14, Lorelei A Mucci1,10. 1. Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. 2. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, Florida. 3. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. 4. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts. 5. Department of Statistics, Ohio State University, Columbus, Ohio. 6. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. 7. Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts. 8. Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. 9. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. 10. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. 11. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 12. Department of Histopathology, St. James's Hospital and Trinity College Dublin Medical School, Dublin, Ireland. 13. Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. 14. Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
Abstract
BACKGROUND: Obese men are at higher risk of advanced prostate cancer and cancer-specific mortality; however, the biology underlying this association remains unclear. This study examined gene expression profiles of prostate tissue to identify biological processes differentially expressed by obesity status and lethal prostate cancer. METHODS: 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-specific 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. RESULTS: 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-weight men; 5 of these were related to chromatin modification and remodeling (false-discovery rate < 0.25). Patients with high tumor expression of chromatin-related genes had worse clinical characteristics (Gleason grade > 7, 41% vs 17%; P = 2 × 10-4 ) and an increased risk of lethal disease that was independent of grade and stage (OR, 5.26; 95% confidence interval, 2.37-12.25). CONCLUSIONS: 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. Cancer 2017;123:4130-4138.
BACKGROUND:Obesemen are at higher risk of advanced prostate cancer and cancer-specific mortality; however, the biology underlying this association remains unclear. This study examined gene expression profiles of prostate tissue to identify biological processes differentially expressed by obesity status and lethal prostate cancer. METHODS: 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-specific 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. RESULTS: 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/obesemen versus healthy-weight men; 5 of these were related to chromatin modification and remodeling (false-discovery rate < 0.25). Patients with high tumor expression of chromatin-related genes had worse clinical characteristics (Gleason grade > 7, 41% vs 17%; P = 2 × 10-4 ) and an increased risk of lethal disease that was independent of grade and stage (OR, 5.26; 95% confidence interval, 2.37-12.25). CONCLUSIONS: 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. Cancer 2017;123:4130-4138.
Authors: Hyun Kim; Ingrid Kalchman; María Santiago-Jiménez; Jonathan Lehrer; Jenny Guo; Gretchen Hermann; Kosj Yamoah; Mohammed Alshalalfa; Huei-Chung Huang; Ashley E Ross; Edward M Schaeffer; Elai Davicioni; Nicholas Erho; Kasra Yousefi; Robert B Den Journal: Cancer Date: 2017-01-31 Impact factor: 6.860
Authors: Aravind Subramanian; Pablo Tamayo; Vamsi K Mootha; Sayan Mukherjee; Benjamin L Ebert; Michael A Gillette; Amanda Paulovich; Scott L Pomeroy; Todd R Golub; Eric S Lander; Jill P Mesirov Journal: Proc Natl Acad Sci U S A Date: 2005-09-30 Impact factor: 11.205
Authors: David B Seligson; Steve Horvath; Tao Shi; Hong Yu; Sheila Tze; Michael Grunstein; Siavash K Kurdistani Journal: Nature Date: 2005-06-30 Impact factor: 49.962
Authors: C H Hennekens; J E Buring; J E Manson; M Stampfer; B Rosner; N R Cook; C Belanger; F LaMotte; J M Gaziano; P M Ridker; W Willett; R Peto Journal: N Engl J Med Date: 1996-05-02 Impact factor: 91.245
Authors: W Weichert; A Röske; V Gekeler; T Beckers; C Stephan; K Jung; F R Fritzsche; S Niesporek; C Denkert; M Dietel; G Kristiansen Journal: Br J Cancer Date: 2008-01-22 Impact factor: 7.640
Authors: Margaret S Pichardo; Cheryl J Smith; Tiffany H Dorsey; Christopher A Loffredo; Stefan Ambs Journal: Cancer Epidemiol Biomarkers Prev Date: 2018-05-21 Impact factor: 4.254
Authors: Konrad H Stopsack; Ericka M Ebot; Mary K Downer; Travis A Gerke; Jennifer R Rider; Philip W Kantoff; Lorelei A Mucci Journal: Cancer Causes Control Date: 2018-06-18 Impact factor: 2.506
Authors: Wei Tang; Tiffany A Wallace; Ming Yi; Cristina Magi-Galluzzi; Tiffany H Dorsey; Olusegun O Onabajo; Adeola Obajemu; Symone V Jordan; Christopher A Loffredo; Robert M Stephens; Robert H Silverman; George R Stark; Eric A Klein; Ludmila Prokunina-Olsson; Stefan Ambs Journal: Clin Cancer Res Date: 2018-07-16 Impact factor: 12.531
Authors: Christopher J Sweeney; Stephen P Finn; Lorelei A Mucci; Emma H Allott; Ericka M Ebot; Konrad H Stopsack; Amparo G Gonzalez-Feliciano; Sarah C Markt; Kathryn M Wilson; Thomas U Ahearn; Travis A Gerke; Mary K Downer; Jennifer R Rider; Stephen J Freedland; Tamara L Lotan; Philip W Kantoff; Elizabeth A Platz; Massimo Loda; Meir J Stampfer; Edward Giovannucci Journal: Clin Cancer Res Date: 2019-11-21 Impact factor: 12.531
Authors: David P Labbé; Giorgia Zadra; Meng Yang; Jaime M Reyes; Charles Y Lin; Stefano Cacciatore; Ericka M Ebot; Amanda L Creech; Francesca Giunchi; Michelangelo Fiorentino; Habiba Elfandy; Sudeepa Syamala; Edward D Karoly; Mohammed Alshalalfa; Nicholas Erho; Ashley Ross; Edward M Schaeffer; Ewan A Gibb; Mandeep Takhar; Robert B Den; Jonathan Lehrer; R Jeffrey Karnes; Stephen J Freedland; Elai Davicioni; Daniel E Spratt; Leigh Ellis; Jacob D Jaffe; Anthony V DʼAmico; Philip W Kantoff; James E Bradner; Lorelei A Mucci; Jorge E Chavarro; Massimo Loda; Myles Brown Journal: Nat Commun Date: 2019-09-25 Impact factor: 14.919