Identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error

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Shipitsin, M ; Small, C ; Choudhury, S ; Giladi, E ; Friedlander, S ; Nardone, J ; Hussain, S ; Hurley, A D ; Ernst, C ; Huang, Y E ; Chang, H ; Nifong, T P ; Rimm, D L ; Dunyak, J ; Loda, M ; Berman, D M ; Blume-Jensen, P (2014)
  • Publisher: Nature Publishing Group
  • Journal: volume 111, issue 6, pages 1,201-1,212 (issn: 0007-0920, eissn: 1532-1827)
  • Related identifiers: doi: 10.1038/bjc.2014.396, doi: 10.1038/bjc.2014.396., pmc: PMC4453845
  • Subject: Molecular Diagnostics | prostate cancer | biomarkers | sampling error | biopsy | prognosis | tumour heterogeneity

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.
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