Evaluation of protein biomarkers of prostate cancer aggressiveness

Anthony E. Rizzardi, Nikolaus K. Rosener, Joe Koopmeiners, Rachel I Vogel, Greg Metzger, Colleen L. Forster, Lauren O. Marston, Jessica R. Tiffany, James B Mc Carthy, Eva A. Turley, Christopher A Warlick, Jonathan C. Henriksen, Stephen C. Schmechel

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number244
JournalBMC Cancer
Volume14
Issue number1
DOIs
StatePublished - Apr 5 2014

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Biomarkers
Prostatectomy
Proteins
Prostatic Neoplasms
Epithelium
Lymph Nodes
Immunohistochemistry
Prostate Cancer, Hereditary, 7
Pathology
Staining and Labeling
Neoplasms
Therapeutics

Keywords

  • Aggressiveness
  • Biomarker
  • Prostate cancer
  • Signature

Cite this

Evaluation of protein biomarkers of prostate cancer aggressiveness. / Rizzardi, Anthony E.; Rosener, Nikolaus K.; Koopmeiners, Joe; Vogel, Rachel I; Metzger, Greg; Forster, Colleen L.; Marston, Lauren O.; Tiffany, Jessica R.; Mc Carthy, James B; Turley, Eva A.; Warlick, Christopher A; Henriksen, Jonathan C.; Schmechel, Stephen C.

In: BMC Cancer, Vol. 14, No. 1, 244, 05.04.2014.

Research output: Contribution to journalArticle

Rizzardi, AE, Rosener, NK, Koopmeiners, J, Vogel, RI, Metzger, G, Forster, CL, Marston, LO, Tiffany, JR, Mc Carthy, JB, Turley, EA, Warlick, CA, Henriksen, JC & Schmechel, SC 2014, 'Evaluation of protein biomarkers of prostate cancer aggressiveness', BMC Cancer, vol. 14, no. 1, 244. https://doi.org/10.1186/1471-2407-14-244
Rizzardi, Anthony E. ; Rosener, Nikolaus K. ; Koopmeiners, Joe ; Vogel, Rachel I ; Metzger, Greg ; Forster, Colleen L. ; Marston, Lauren O. ; Tiffany, Jessica R. ; Mc Carthy, James B ; Turley, Eva A. ; Warlick, Christopher A ; Henriksen, Jonathan C. ; Schmechel, Stephen C. / Evaluation of protein biomarkers of prostate cancer aggressiveness. In: BMC Cancer. 2014 ; Vol. 14, No. 1.
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AU - Rizzardi, Anthony E.

AU - Rosener, Nikolaus K.

AU - Koopmeiners, Joe

AU - Vogel, Rachel I

AU - Metzger, Greg

AU - Forster, Colleen L.

AU - Marston, Lauren O.

AU - Tiffany, Jessica R.

AU - Mc Carthy, James B

AU - Turley, Eva A.

AU - Warlick, Christopher A

AU - Henriksen, Jonathan C.

AU - Schmechel, Stephen C.

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AB - 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.

KW - Aggressiveness

KW - Biomarker

KW - Prostate cancer

KW - Signature

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