title: The Thoc1 ribonucleoprotein and prostate cancer progression.
abstract: BACKGROUND
  The majority of newly diagnosed prostate cancers will remain indolent, but distinguishing between aggressive and indolent disease is imprecise. This has led to the important clinical problem of overtreatment. THOC1 encodes a nuclear ribonucleoprotein whose expression is higher in some cancers than in normal tissue. The hypothesis that THOC1 may be a functionally relevant biomarker that can improve the identification of aggressive prostate cancer has not been tested.
  
  
  METHODS
  THOC1 protein immunostaining was evaluated in a retrospective collection of more than 700 human prostate cancer specimens and the results associated with clinical variables and outcome. Thoc1 was conditionally deleted in an autochthonous mouse model (n = 22 or 23 per genotype) to test whether it is required for prostate cancer progression. All statistical tests were two-sided.
  
  
  RESULTS
  THOC1 protein immunostaining increases with higher Gleason score and more advanced Tumor/Node/Metastasis stage. Time to biochemical recurrence is statistically significantly shorter for cancers with high THOC1 protein (log-rank P = .002, and it remains statistically significantly associated with biochemical recurrence after adjusting for Gleason score, clinical stage, and prostate-specific antigen levels (hazard ratio = 1.61, 95% confidence interval = 1.03 to 2.51, P = .04). Thoc1 deletion prevents prostate cancer progression in mice, but has little effect on normal tissue. Prostate cancer cells deprived of Thoc1 show gene expression defects that compromise cell growth.
  
  
  CONCLUSIONS
  Thoc1 is required to support the unique gene expression requirements of aggressive prostate cancer in mice. In humans, high THOC1 protein immunostaining associates with prostate cancer aggressiveness and recurrence. Thus, THOC1 protein is a functionally relevant molecular marker that may improve the identification of aggressive prostate cancers, potentially reducing overtreatment.
authors.affiliation: Department of Pharmacology & Therapeutics (MC, YW, XZ, BAF, DWG), Department of Biostatistics (DLG), Department of Pathology (TK, WB, CDM), Department of Cancer Prevention and Population Science (RDPO), Department of Urology (JLM), Roswell Park Cancer Institute, Buffalo, NY; Department of Biomedical Sciences, Cornell University, Ithaca, NY (AYN); Department of Pathology, Virginia Commonwealth University, Richmond, VA (YL). Current affiliation: MedImmune LLC, Gaitherburg, MD.
authors.forename: Meenalakshmi
authors.initials: M
authors.lastname: Chinnam
authors.affiliation: Department of Pharmacology & Therapeutics (MC, YW, XZ, BAF, DWG), Department of Biostatistics (DLG), Department of Pathology (TK, WB, CDM), Department of Cancer Prevention and Population Science (RDPO), Department of Urology (JLM), Roswell Park Cancer Institute, Buffalo, NY; Department of Biomedical Sciences, Cornell University, Ithaca, NY (AYN); Department of Pathology, Virginia Commonwealth University, Richmond, VA (YL). Current affiliation: MedImmune LLC, Gaitherburg, MD.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology & Therapeutics (MC, YW, XZ, BAF, DWG), Department of Biostatistics (DLG), Department of Pathology (TK, WB, CDM), Department of Cancer Prevention and Population Science (RDPO), Department of Urology (JLM), Roswell Park Cancer Institute, Buffalo, NY; Department of Biomedical Sciences, Cornell University, Ithaca, NY (AYN); Department of Pathology, Virginia Commonwealth University, Richmond, VA (YL). Current affiliation: MedImmune LLC, Gaitherburg, MD.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Current affiliation: MedImmune LLC, Gaitherburg, MD.
authors.forename: David L
authors.initials: DL
authors.lastname: Gold
authors.affiliation: Department of Pharmacology & Therapeutics (MC, YW, XZ, BAF, DWG), Department of Biostatistics (DLG), Department of Pathology (TK, WB, CDM), Department of Cancer Prevention and Population Science (RDPO), Department of Urology (JLM), Roswell Park Cancer Institute, Buffalo, NY; Department of Biomedical Sciences, Cornell University, Ithaca, NY (AYN); Department of Pathology, Virginia Commonwealth University, Richmond, VA (YL). Current affiliation: MedImmune LLC, Gaitherburg, MD.
authors.forename: Thaer
authors.initials: T
authors.lastname: Khoury
authors.affiliation: Department of Pharmacology & Therapeutics (MC, YW, XZ, BAF, DWG), Department of Biostatistics (DLG), Department of Pathology (TK, WB, CDM), Department of Cancer Prevention and Population Science (RDPO), Department of Urology (JLM), Roswell Park Cancer Institute, Buffalo, NY; Department of Biomedical Sciences, Cornell University, Ithaca, NY (AYN); Department of Pathology, Virginia Commonwealth University, Richmond, VA (YL). Current affiliation: MedImmune LLC, Gaitherburg, MD.
authors.forename: Alexander Yu
authors.initials: AY
authors.lastname: Nikitin
authors.affiliation: Department of Pharmacology & Therapeutics (MC, YW, XZ, BAF, DWG), Department of Biostatistics (DLG), Department of Pathology (TK, WB, CDM), Department of Cancer Prevention and Population Science (RDPO), Department of Urology (JLM), Roswell Park Cancer Institute, Buffalo, NY; Department of Biomedical Sciences, Cornell University, Ithaca, NY (AYN); Department of Pathology, Virginia Commonwealth University, Richmond, VA (YL). Current affiliation: MedImmune LLC, Gaitherburg, MD.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Foster
authors.affiliation: Department of Pharmacology & Therapeutics (MC, YW, XZ, BAF, DWG), Department of Biostatistics (DLG), Department of Pathology (TK, WB, CDM), Department of Cancer Prevention and Population Science (RDPO), Department of Urology (JLM), Roswell Park Cancer Institute, Buffalo, NY; Department of Biomedical Sciences, Cornell University, Ithaca, NY (AYN); Department of Pathology, Virginia Commonwealth University, Richmond, VA (YL). Current affiliation: MedImmune LLC, Gaitherburg, MD.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology & Therapeutics (MC, YW, XZ, BAF, DWG), Department of Biostatistics (DLG), Department of Pathology (TK, WB, CDM), Department of Cancer Prevention and Population Science (RDPO), Department of Urology (JLM), Roswell Park Cancer Institute, Buffalo, NY; Department of Biomedical Sciences, Cornell University, Ithaca, NY (AYN); Department of Pathology, Virginia Commonwealth University, Richmond, VA (YL). Current affiliation: MedImmune LLC, Gaitherburg, MD.
authors.forename: Wiam
authors.initials: W
authors.lastname: Bshara
authors.affiliation: Department of Pharmacology & Therapeutics (MC, YW, XZ, BAF, DWG), Department of Biostatistics (DLG), Department of Pathology (TK, WB, CDM), Department of Cancer Prevention and Population Science (RDPO), Department of Urology (JLM), Roswell Park Cancer Institute, Buffalo, NY; Department of Biomedical Sciences, Cornell University, Ithaca, NY (AYN); Department of Pathology, Virginia Commonwealth University, Richmond, VA (YL). Current affiliation: MedImmune LLC, Gaitherburg, MD.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Morrison
authors.affiliation: Department of Pharmacology & Therapeutics (MC, YW, XZ, BAF, DWG), Department of Biostatistics (DLG), Department of Pathology (TK, WB, CDM), Department of Cancer Prevention and Population Science (RDPO), Department of Urology (JLM), Roswell Park Cancer Institute, Buffalo, NY; Department of Biomedical Sciences, Cornell University, Ithaca, NY (AYN); Department of Pathology, Virginia Commonwealth University, Richmond, VA (YL). Current affiliation: MedImmune LLC, Gaitherburg, MD.
authors.forename: Rochelle D
authors.initials: RD
authors.lastname: Payne Ondracek
authors.affiliation: Department of Pharmacology & Therapeutics (MC, YW, XZ, BAF, DWG), Department of Biostatistics (DLG), Department of Pathology (TK, WB, CDM), Department of Cancer Prevention and Population Science (RDPO), Department of Urology (JLM), Roswell Park Cancer Institute, Buffalo, NY; Department of Biomedical Sciences, Cornell University, Ithaca, NY (AYN); Department of Pathology, Virginia Commonwealth University, Richmond, VA (YL). Current affiliation: MedImmune LLC, Gaitherburg, MD.
authors.forename: James L
authors.initials: JL
authors.lastname: Mohler
authors.affiliation: Department of Pharmacology & Therapeutics (MC, YW, XZ, BAF, DWG), Department of Biostatistics (DLG), Department of Pathology (TK, WB, CDM), Department of Cancer Prevention and Population Science (RDPO), Department of Urology (JLM), Roswell Park Cancer Institute, Buffalo, NY; Department of Biomedical Sciences, Cornell University, Ithaca, NY (AYN); Department of Pathology, Virginia Commonwealth University, Richmond, VA (YL). Current affiliation: MedImmune LLC, Gaitherburg, MD. david.goodrich@roswellpark.org.
authors.forename: David W
authors.initials: DW
authors.lastname: Goodrich
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood*; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000175:diagnosis; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C400546:THOC1 protein, human; C511176:Thoc1 protein, mouse; D017430:Prostate-Specific Antigen