Boolean analysis identifies CD38 as a biomarker of aggressive localized prostate cancer
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Debashis Sahoo1, Wei Wei2, Heidi Auman3, Antonio Hurtado-Coll4, Peter R. Carroll5, Ladan Fazli4, Martin E. Gleave4, Daniel W. Lin6, Peter S. Nelson7, Jeff Simko8, Ian M. Thompson9, Robin J. Leach10, Dean A. Troyer11, Lawrence D. True12, Jesse K. McKenney13, Ziding Feng2 and James D. Brooks14
1Department of Pediatrics and Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA
2The Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3Canary Foundation, Canary Center at Stanford, Palo Alto, CA, USA
4The Prostate Center at Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada
5Department of Urology, University of California San Francisco, San Francisco, CA, USA
6Department of Urology, University of Washington Medical Center, Seattle, WA, USA
7Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
8Department of Pathology, University of California San Francisco, San Francisco, CA, USA
9CHRISTUS Medical Center Hospital, San Antonio, Texas, USA
10Department of Urology, University of Texas Health at San Antonio, San Antonio, TX, USA
11Eastern Virginia Medical School, Pathology, Microbiology and Molecular Biology, Norfolk, VA, USA
12Department of Pathology, University of Washington Medical Center, Seattle, WA, USA
13Department of Pathology, Cleveland Clinic, Cleveland, OH, USA
14Department of Urology, Stanford University, Stanford, CA, USA
James D. Brooks, email: [email protected]
Keywords: Prostate cancer; CD38; ARG2; Prognosis; biochemical recurrence
Received: November 20, 2017 Accepted: December 23, 2017 Published: January 05, 2018
The introduction of serum Prostate Specific Antigen (PSA) testing nearly 30 years ago has been associated with a significant shift towards localized disease and decreased deaths due to prostate cancer. Recognition that PSA testing has caused over diagnosis and over treatment of prostate cancer has generated considerable controversy over its value, and has spurred efforts to identify prognostic biomarkers to distinguish patients who need treatment from those that can be observed. Recent studies show that cancer is heterogeneous and forms a hierarchy of tumor cell populations. We developed a method of identifying prostate cancer differentiation states related to androgen signaling using Boolean logic. Using gene expression data, we identified two markers, CD38 and ARG2, that group prostate cancer into three differentiation states. Cancers with CD38-, ARG2- expression patterns, corresponding to an undifferentiated state, had significantly lower 10-year recurrence-free survival compared to the most differentiated group (CD38+ARG2+). We carried out immunohistochemical (IHC) staining for these two markers in a single institution (Stanford; n = 234) and multi-institution (Canary; n = 1326) cohorts. IHC staining for CD38 and ARG2 in the Stanford cohort demonstrated that combined expression of CD38 and ARG2 was prognostic. In the Canary cohort, low CD38 protein expression by IHC was significantly associated with recurrence-free survival (RFS), seminal vesicle invasion (SVI), extra-capsular extension (ECE) in univariable analysis. In multivariable analysis, ARG2 and CD38 IHC staining results were not independently associated with RFS, overall survival, or disease-specific survival after adjusting for other factors including SVI, ECE, Gleason score, pre-operative PSA, and surgical margins.
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