title: Identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error.
abstract: BACKGROUND
  Key challenges of biopsy-based determination of prostate cancer aggressiveness include tumour heterogeneity, biopsy-sampling error, and variations in biopsy interpretation. The resulting uncertainty in risk assessment leads to significant overtreatment, with associated costs and morbidity. We developed a performance-based strategy to identify protein biomarkers predictive of prostate cancer aggressiveness and lethality regardless of biopsy-sampling variation.
  
  
  METHODS
  Prostatectomy samples from a large patient cohort with long follow-up were blindly assessed by expert pathologists who identified the tissue regions with the highest and lowest Gleason grade from each patient. To simulate biopsy-sampling error, a core from a high- and a low-Gleason area from each patient sample was used to generate a 'high' and a 'low' tumour microarray, respectively.
  
  
  RESULTS
  Using a quantitative proteomics approach, we identified from 160 candidates 12 biomarkers that predicted prostate cancer aggressiveness (surgical Gleason and TNM stage) and lethal outcome robustly in both high- and low-Gleason areas. Conversely, a previously reported lethal outcome-predictive marker signature for prostatectomy tissue was unable to perform under circumstances of maximal sampling error.
  
  
  CONCLUSIONS
  Our results have important implications for cancer biomarker discovery in general and development of a sampling error-resistant clinical biopsy test for prediction of prostate cancer aggressiveness.
authors.affiliation: Metamark Genetics Inc., Cambridge, MA 02142, USA.
authors.forename: M
authors.initials: M
authors.lastname: Shipitsin
authors.affiliation: Metamark Genetics Inc., Cambridge, MA 02142, USA.
authors.forename: C
authors.initials: C
authors.lastname: Small
authors.affiliation: Metamark Genetics Inc., Cambridge, MA 02142, USA.
authors.forename: S
authors.initials: S
authors.lastname: Choudhury
authors.affiliation: Metamark Genetics Inc., Cambridge, MA 02142, USA.
authors.forename: E
authors.initials: E
authors.lastname: Giladi
authors.affiliation: Metamark Genetics Inc., Cambridge, MA 02142, USA.
authors.forename: S
authors.initials: S
authors.lastname: Friedlander
authors.affiliation: Metamark Genetics Inc., Cambridge, MA 02142, USA.
authors.forename: J
authors.initials: J
authors.lastname: Nardone
authors.affiliation: Metamark Genetics Inc., Cambridge, MA 02142, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Metamark Genetics Inc., Cambridge, MA 02142, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Hurley
authors.affiliation: Metamark Genetics Inc., Cambridge, MA 02142, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ernst
authors.affiliation: Metamark Genetics Inc., Cambridge, MA 02142, USA.
authors.forename: Y E
authors.initials: YE
authors.lastname: Huang
authors.affiliation: Metamark Genetics Inc., Cambridge, MA 02142, USA.
authors.forename: H
authors.initials: H
authors.lastname: Chang
authors.affiliation: Metamark Genetics Inc., Cambridge, MA 02142, USA.
authors.forename: T P
authors.initials: TP
authors.lastname: Nifong
authors.affiliation: Department of Pathology, Yale University Medical School, New Haven, CT 06520, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Rimm
authors.affiliation: Metamark Genetics Inc., Cambridge, MA 02142, USA.
authors.forename: J
authors.initials: J
authors.lastname: Dunyak
authors.affiliation: Department of Pathology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: M
authors.initials: M
authors.lastname: Loda
authors.affiliation: Department of Pathology and Molecular Medicine and Queen's Cancer Research Institute, Queen's University, Kingston, ON, Canada K7L 3N6.
authors.forename: D M
authors.initials: DM
authors.lastname: Berman
authors.affiliation: Metamark Genetics Inc., Cambridge, MA 02142, USA.
authors.forename: P
authors.initials: P
authors.lastname: Blume-Jensen
mesh_terms: D000185:Actinin / Q000032:analysis; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000032:analysis; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis*; D044963:Biopsy, Fine-Needle; D044842:Cullin Proteins / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D005500:Follow-Up Studies; D018840:HSP70 Heat-Shock Proteins / Q000032:analysis; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000032:analysis; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010766:Phosphorylation; D011467:Prostate / Q000737:chemistry / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000401:mortality* / Q000473:pathology*; D040901:Proteomics; D034702:RNA-Binding Protein FUS; D012372:ROC Curve; D038601:Ribosomal Protein S6 / Q000032:analysis / Q000378:metabolism; D015983:Selection Bias; D051899:Smad2 Protein / Q000032:analysis; D051901:Smad4 Protein / Q000032:analysis; D046888:Tissue Array Analysis; D050995:Voltage-Dependent Anion Channel 1 / Q000032:analysis; D051840:Y-Box-Binding Protein 1 / Q000032:analysis
chemical_list: C526905:ACTN1 protein, human; D014408:Biomarkers, Tumor; C105153:CUL2 protein, human; D044842:Cullin Proteins; C487709:DERL1 protein, human; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; C492001:HSPA9 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C104382:PLAG1 protein, human; D034702:RNA-Binding Protein FUS; D038601:Ribosomal Protein S6; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051901:Smad4 Protein; C494762:VDAC1 protein, human; D051840:Y-Box-Binding Protein 1; D000185:Actinin; D050995:Voltage-Dependent Anion Channel 1; D019883:Alkyl and Aryl Transferases; C540142:prenyl diphosphate synthase, subunit 2, human