title: mRNA expression signature of Gleason grade predicts lethal prostate cancer.
abstract: OBJECTIVE
  Prostate-specific antigen screening has led to enormous overtreatment of prostate cancer because of the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and the most indeterminate in terms of prognosis.
  
  
  METHODS
  Using the complementary DNA-mediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (n = 358) and Physicians' Health Study (PHS; n = 109). We developed an mRNA signature of Gleason grade comparing individuals with Gleason ≤ 6 to those with Gleason ≥ 8 tumors and applied the model among patients with Gleason 7 to discriminate lethal cases.
  
  
  RESULTS
  We built a 157-gene signature using the Swedish data that predicted Gleason with low misclassification (area under the curve [AUC] = 0.91); when this signature was tested in the PHS, the discriminatory ability remained high (AUC = 0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4 + 3 or 3 + 4 (P = .006).
  
  
  CONCLUSIONS
  Our expression signature and the genes identified may improve our understanding of the de-differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment.
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115, USA. kpenney@hsph.harvard.edu
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Penney
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Sinnott
authors.forename: Katja
authors.initials: K
authors.lastname: Fall
authors.forename: Yudi
authors.initials: Y
authors.lastname: Pawitan
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Stark
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Fiorentino
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.forename: Stephen
authors.initials: S
authors.lastname: Finn
authors.forename: Stefano
authors.initials: S
authors.lastname: Calza
authors.forename: Richard
authors.initials: R
authors.lastname: Flavin
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Freedman
authors.forename: Sunita
authors.initials: S
authors.lastname: Setlur
authors.forename: Howard D
authors.initials: HD
authors.lastname: Sesso
authors.forename: Swen-Olof
authors.initials: SO
authors.lastname: Andersson
authors.forename: Neil
authors.initials: N
authors.lastname: Martin
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: Jan-Erik
authors.initials: JE
authors.lastname: Johansson
authors.forename: Hans-Olov
authors.initials: HO
authors.lastname: Adami
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Ove
authors.initials: O
authors.lastname: Andrén
authors.forename: Meir J
authors.initials: MJ
authors.lastname: Stampfer
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation; D018450:Disease Progression; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*