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Measuring PI3K activation in prostate cancer
1
Title: Measuring PI3K Activation: Clinicopathologic, Immunohistochemical, and RNA
Expression Analysis in Prostate Cancer
Authors: Neil E Martin*1, Travis Gerke2, Jennifer A Sinnott2,7, Edward C Stack3.8,9, Ove Andrén4,
Swen-Olof Andersson4, Jan-Erik Johansson4, Michelangelo Fiorentino3,5, Stephen Finn3,6,
Giuseppe Fedele3, Meir Stampfer2,7, Philip W Kantoff9, Lorelei A Mucci2,7, Massimo Loda3,8-11
1. Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
2. Department of Epidemiology, Harvard School of Public Health, Boston MA 3. Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 4. School of Health and Medical Sciences, Örebro University; and Department of Urology,
Örebro University Hospital, Örebro, Sweden 5. Pathology Unit, Addarii Institute, S Orsola-Malpighi Hospital, Bologna, Italy 6. Department of Pathology, Trinity College, Dublin, Ireland 7. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s
Hospital, and Harvard Medical School, Boston, MA 8. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School,
Boston, MA 9. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical
School, Boston, MA 10. Broad Institute of Harvard and MIT, Cambridge, MA, USA 11. Division of Cancer Studies, King’s College London, London, UK.
Running Title: Measuring PI3K activation in prostate cancer
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Department of Radiation Oncology Brigham and Women’s Hospital/Dana-Farber Cancer Institute 75 Francis St, ASB-I, L2 Boston, MA 02115 Phone: 617-732-7948 Fax: 617-264-5242 [email protected] Conflicts of interest: None of the authors have any conflicts of interest. Abstract: 245/250 Word Count: 4437/5000 Number of Figures and Tables: 6
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
this study was approved by the Connecticut Department of Public Health (DPH) Human
Investigations Committee. Certain data used in this publication were obtained from the
DPH. The authors assume full responsibility for analyses and interpretation of these data.
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§Lethal outcome missing in 118 missing due to insufficient follow-up (minimum of 8 years without a lethal or metastatic event) Table 1: Baseline clinical characteristics and outcomes for the three prostate cancer cohorts
PMAIP1 phorbol-12-myristate-13-acetate-induced protein 1 P53, DNA damage response, apoptosis
FANCC Fanconi anemia, complementation group C DNA repair, RLF rearranged L-myc fusion transcription regulation
RREB1 ras responsive element binding protein 1 Ras signaling; transcription regulation
NUSAP1 nucleolar and spindle associated protein 1 cell cycle regulation TK1 thymidine kinase 1, soluble pyrmidine metabolsm
do wn DPT dermatopontin cell proliferation, cell adhesion
WFS1 Wolfram syndrome 1 protein processing
Gene sets Set adjusted pCell cycle progression (35) <0.001KEGG mismatch repair 0.15Saal (9) 0.15KEGG oocyte meiosis 0.34KEGG progesterone mediate oocyte maturation 0.34KEGG regulation of actin cytoskeleton 0.34KEGG prostate cancer 0.34KEGG dilated cardiomyopathy 0.48KEGG hypertrophic cardiomyopathy 0.49KEGG sphingolipid metabolism 0.56Table 2: Genes significantly differentially expressed between the low and high PI3K tumors as defined by the 4-marker immunohistochemical score and the top 10 gene sets differentially expressed between the two groups.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569
Published OnlineFirst June 29, 2015.Mol Cancer Res Neil E Martin, Travis Gerke, Jennifer A Sinnott, et al. Prostate CancerImmunohistochemical, and RNA Expression Analysis in Measuring PI3K Activation: Clinicopathologic,
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Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 29, 2015; DOI: 10.1158/1541-7786.MCR-14-0569