title: SPINK1 Defines a Molecular Subtype of Prostate Cancer in Men with More Rapid Progression in an at Risk, Natural History Radical Prostatectomy Cohort.
abstract: Prostate cancer is clinically and molecularly heterogeneous. We determined the prognosis of men with ERG-ETS fusions and SPINK1 over expression.
  
  
  
  Men were identified with intermediate or high risk localized prostate cancer treated with radical prostatectomy and no therapy before metastasis. A case-cohort design sampled a cohort (262) enriched with metastasis from the entire cohort and a cohort (213) enriched with metastasis from patients with biochemical recurrence. We analyzed transcriptomic profiles and subtyped tumors as m-ERG+, m-ETS+, m-SPINK1+or Triple Negative (m-ERG─/m-ETS─/m-SPINK1─), and multivariable logistic regression analyses, Kaplan-Meier and multivariable Cox models were used to evaluate subtypes as predictors of clinical outcomes.
  
  
  
  Overall 36%, 13%, 11% and 40% of prostate cancer was classified as m-ERG+, m-ETS+, m-SPINK1+and Triple Negative, respectively. Univariable analysis demonstrated that m-SPINK1+tumors were more common in African-American men (OR 5, 95% CI 1.6-16) but less commonly associated with positive surgical margins (OR 0.16, 95% CI 0.03-0.69) compared to the m-ERG+group. Compared to the Triple Negative group, m-SPINK1+showed similar associations with race and surgical margins in univariable and multivariable analyses across the entire cohort. Survival analyses did not show significant differences among m-ERG+, m-ETS+and Triple Negative cases. m-SPINK1+independently predicted prostate cancer specific mortality after metastasis (HR 2.48, 95% CI 0.96-6.4) and biochemical recurrence (HR 3, 95% CI 1.1-8).
  
  
  
  SPINK1 over expression is associated with prostate cancer specific mortality in at risk men with biochemical and clinical recurrence after prostatectomy. ERG-ETS alterations are not prognostic for outcome.
authors.affiliation: James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Johnson
authors.affiliation: James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Ross
authors.affiliation: GenomeDx Biosciences, Vancouver, British Columbia, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alshalalfa
authors.affiliation: GenomeDx Biosciences, Vancouver, British Columbia, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Erho
authors.affiliation: GenomeDx Biosciences, Vancouver, British Columbia, Canada.
authors.forename: Kasra
authors.initials: K
authors.lastname: Yousefi
authors.affiliation: James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Glavaris
authors.affiliation: James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Helen
authors.initials: H
authors.lastname: Fedor
authors.affiliation: James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Misop
authors.initials: M
authors.lastname: Han
authors.affiliation: James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Sheila F
authors.initials: SF
authors.lastname: Faraj
authors.affiliation: James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Stephania M
authors.initials: SM
authors.lastname: Bezerra
authors.affiliation: James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: George
authors.initials: G
authors.lastname: Netto
authors.affiliation: James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Alan W
authors.initials: AW
authors.lastname: Partin
authors.affiliation: James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Trock
authors.affiliation: GenomeDx Biosciences, Vancouver, British Columbia, Canada.
authors.forename: Elai
authors.initials: E
authors.lastname: Davicioni
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address: eschaeffer@jhmi.edu.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schaeffer
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D018450:Disease Progression; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D011468:Prostatectomy / Q000379:methods; D011471:Prostatic Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D014359:Trypsin Inhibitor, Kazal Pancreatic / Q000235:genetics*
chemical_list: C486642:SPINK1 protein, human; D014359:Trypsin Inhibitor, Kazal Pancreatic
keywords: genomics; neoplasm metastasis; prognosis; prostatic neoplasms; transcriptome