Evaluation of protein biomarkers of prostate cancer aggressiveness.
BACKGROUND
Prognostic multibiomarker signatures in prostate cancer (PCa) may improve patient management and provide a bridge for developing novel therapeutics and imaging methods. Our objective was to evaluate the association between expression of 33 candidate protein biomarkers and time to biochemical failure (BF) after prostatectomy.


METHODS
PCa tissue microarrays were constructed representing 160 patients for whom clinicopathologic features and follow-up data after surgery were available. Immunohistochemistry for each of 33 proteins was quantified using automated digital pathology techniques. Relationships between clinicopathologic features, staining intensity, and time to BF were assessed. Predictive modeling using multiple imputed datasets was performed to identify the top biomarker candidates.


RESULTS
In univariate analyses, lymph node positivity, surgical margin positivity, non-localized tumor, age at prostatectomy, and biomarkers CCND1, HMMR, IGF1, MKI67, SIAH2, and SMAD4 in malignant epithelium were significantly associated with time to BF. HMMR, IGF1, and SMAD4 remained significantly associated with BF after adjusting for clinicopathologic features while additional associations were observed for HOXC6 and MAP4K4 following adjustment. In multibiomarker predictive models, 3 proteins including HMMR, SIAH2, and SMAD4 were consistently represented among the top 2, 3, 4, and 5 most predictive biomarkers, and a signature comprised of these proteins best predicted BF at 3 and 5 years.


CONCLUSIONS
This study provides rationale for investigation of HMMR, HOXC6, IGF1, MAP4K4, SIAH2, and SMAD4 as biomarkers of PCa aggressiveness in larger cohorts.
Anthony E
AE
Rizzardi
Nikolaus K
NK
Rosener
Joseph S
JS
Koopmeiners
Rachel
R
Isaksson Vogel
Gregory J
GJ
Metzger
Colleen L
CL
Forster
Lauren O
LO
Marston
Jessica R
JR
Tiffany
James B
JB
McCarthy
Eva A
EA
Turley
Christopher A
CA
Warlick
Jonathan C
JC
Henriksen
Department of Pathology, University of Washington, Mailcode 359791, 908 Jefferson St, Seattle, WA 98104, USA. sschmech@uw.edu.
Stephen C
SC
Schmechel
D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009367:Neoplasm Staging; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D046888:Tissue Array Analysis
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D017430:Prostate-Specific Antigen