title: Evaluation of ERG and SPINK1 by Immunohistochemical Staining and Clinicopathological Outcomes in a Multi-Institutional Radical Prostatectomy Cohort of 1067 Patients.
abstract: Distinguishing between patients with early stage, screen detected prostate cancer who must be treated from those that can be safely watched has become a major issue in prostate cancer care. Identification of molecular subtypes of prostate cancer has opened the opportunity for testing whether biomarkers that characterize these subtypes can be used as biomarkers of prognosis. Two established molecular subtypes are identified by high expression of the ERG oncoprotein, due to structural DNA alterations that encode for fusion transcripts in approximately ½ of prostate cancers, and over-expression of SPINK1, which is purportedly found only in ERG-negative tumors. We used a multi-institutional prostate cancer tissue microarray constructed from radical prostatectomy samples with associated detailed clinical data and with rigorous selection of recurrent and non-recurrent cases to test the prognostic value of immunohistochemistry staining results for the ERG and SPINK1 proteins. In univariate analysis, ERG positive cases (419/1067; 39%) were associated with lower patient age, pre-operative serum PSA levels, lower Gleason scores (≤ 3+4=7) and improved recurrence free survival (RFS). On multivariate analysis, ERG status was not correlated with RFS, disease specific survival (DSS) or overall survival (OS). High-level SPINK1 protein expression (33/1067 cases; 3%) was associated with improved RFS on univariate and multivariate Cox regression analysis. Over-expression of either protein was not associated with clinical outcome. While expression of ERG and SPINK1 proteins was inversely correlated, it was not mutually exclusive since 3 (0.28%) cases showed high expression of both. While ERG and SPINK1 appear to identify discrete molecular subtypes of prostate cancer, only high expression of SPINK1 was associated with improved clinical outcome. However, by themselves, neither ERG nor SPINK1 appear to be useful biomarkers for prognostication of early stage prostate cancer.
authors.affiliation: Department of Urology, Stanford University, Stanford, California, United States of America.
authors.forename: James D
authors.initials: JD
authors.lastname: Brooks
authors.affiliation: The Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Canary Foundation, Canary Center at Stanford, Palo Alto, California, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hawley
authors.affiliation: Canary Foundation, Canary Center at Stanford, Palo Alto, California, United States of America.
authors.forename: Heidi
authors.initials: H
authors.lastname: Auman
authors.affiliation: Department of Urology, University of Washington Medical Center, Seattle, Washington, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Newcomb
authors.affiliation: The Prostate Center at Vancouver General Hospital, University of British Columbia, Vancouver, Canada.
authors.forename: Hilary
authors.initials: H
authors.lastname: Boyer
authors.affiliation: The Prostate Center at Vancouver General Hospital, University of British Columbia, Vancouver, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Jeff
authors.initials: J
authors.lastname: Simko
authors.affiliation: Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Antonio
authors.initials: A
authors.lastname: Hurtado-Coll
authors.affiliation: Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America; Eastern Virginia Medical School, Pathology, Microbiology and Molecular Biology, Norfolk, Virginia, United States of America.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Troyer
authors.affiliation: Department of Urology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Carroll
authors.affiliation: The Prostate Center at Vancouver General Hospital, University of British Columbia, Vancouver, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.affiliation: Department of Urology, Eastern Virginia Medical School, Norfolk, Virginia, United States of America.
authors.forename: Raymond
authors.initials: R
authors.lastname: Lance
authors.affiliation: Department of Urology, University of Washington Medical Center, Seattle, Washington, United States of America.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Lin
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Thompson
authors.affiliation: Department of Pathology, University of Washington Medical Center, Seattle, Washington, United States of America.
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: True
authors.affiliation: The Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Ziding
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Pathology, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Jesse K
authors.initials: JK
authors.lastname: McKenney
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D015331:Cohort Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery*; D013194:Staining and Labeling; D015534:Trans-Activators / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG; D016896:Treatment Outcome; D014359:Trypsin Inhibitor, Kazal Pancreatic
chemical_list: D014408:Biomarkers, Tumor; D002352:Carrier Proteins; C072312:ERG protein, human; C486642:SPINK1 protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014359:Trypsin Inhibitor, Kazal Pancreatic