title: Modification of the association between obesity and lethal prostate cancer by TMPRSS2:ERG.
abstract: BACKGROUND
  TMPRSS2:ERG is a hormonally regulated gene fusion present in about half of prostate tumors. We investigated whether obesity, which deregulates several hormonal pathways, interacts with TMPRSS2:ERG to impact prostate cancer outcomes.
  
  
  METHODS
  The study included 1243 participants in the prospective Physicians' Health Study and Health Professionals Follow-Up Study diagnosed with prostate cancer between 1982 and 2005. ERG overexpression (a TMPRSS2:ERG marker) was assessed by immunohistochemistry of tumor tissue from radical prostatectomy or transurethral resection of the prostate. Body mass index (BMI) and waist circumference, measured on average 1.3 years and 5.3 years before diagnosis, respectively, were available from questionnaires. Data on BMI at baseline was also available. We used Cox regression to calculate hazard ratios and 95% confidence intervals (CIs). All statistical tests were two-sided.
  
  
  RESULTS
  During a mean follow-up of 12.8 years, 119 men developed lethal disease (distant metastases or prostate cancer death). Among men with ERG-positive tumors, the multivariable hazard ratio for lethal prostate cancer was 1.48 (95% CI = 0.98 to 2.23) per 5-unit increase in BMI before diagnosis, 2.51 (95% CI = 1.26 to 4.99) per 8-inch increase in waist circumference before diagnosis, and 2.22 (95% CI = 1.35 to 3.63) per 5-unit increase in BMI at baseline. The corresponding hazard ratios among men with ERG-negative tumors were 1.10 (95% CI = 0.76 to1.59; P interaction = .24), 1.14 (95% CI = 0.62 to 2.10; P interaction = .09), and 0.78 (95% CI = 0.52 to 1.19; P interaction = .001).
  
  
  CONCLUSIONS
  These results suggest that obesity is linked with poorer prostate cancer prognosis primarily in men with tumors harboring the gene fusion TMPRSS2:ERG.
authors.affiliation: Affiliations of authors: Department of Epidemiology (AP, AM, MF, REG, KLP, JRR, EJN, MJS, ELG, LAM) and Department of Nutrition (MJS, ELG), Harvard School of Public Health, Boston, MA; Channing Division of Network Medicine (AP, KLP, JRR, MJS, ELG, LAM) and Division of Preventive Medicine (HDS) , Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Pathology, Brigham and Women's Hospital, Boston, MA (RTL, ECS, ML); Center for Molecular Oncologic Pathology (RTL, RF, ECS, MF, SF, NEM, ML), Department of Radiation Oncology (NEM), and Lank Center for Genitourinary Oncology (PWK), Dana-Farber Cancer Institute, Boston, MA; University of Dublin, Trinity College, Dublin, Ireland (RF, SF); Pathology Unit, Addarii Institute, S. Orsola-Malpighi Hospital, Bologna, Italy (MF); Department of Medicine, McGill University, Montreal, QC, Canada (MP).
authors.forename: Andreas
authors.initials: A
authors.lastname: Pettersson
authors.forename: Rosina T
authors.initials: RT
authors.lastname: Lis
authors.forename: Allison
authors.initials: A
authors.lastname: Meisner
authors.forename: Richard
authors.initials: R
authors.lastname: Flavin
authors.forename: Edward C
authors.initials: EC
authors.lastname: Stack
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Fiorentino
authors.forename: Stephen
authors.initials: S
authors.lastname: Finn
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Graff
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Penney
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Rider
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Nuttall
authors.forename: Neil E
authors.initials: NE
authors.lastname: Martin
authors.forename: Howard D
authors.initials: HD
authors.lastname: Sesso
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.forename: Meir J
authors.initials: MJ
authors.lastname: Stampfer
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D015992:Body Mass Index; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications*; D016017:Odds Ratio; D015514:Oncogene Proteins, Fusion / Q000032:analysis*; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011468:Prostatectomy / Q000379:methods; D011471:Prostatic Neoplasms / Q000737:chemistry* / Q000209:etiology / Q000401:mortality / Q000601:surgery; D011795:Surveys and Questionnaires; D015854:Up-Regulation; D055105:Waist Circumference
chemical_list: D014408:Biomarkers, Tumor; D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human