A Prospective Investigation of PTEN Loss and ERG Expression in Lethal Prostate Cancer

J Natl Cancer Inst. 2015 Nov 27;108(2):djv346. doi: 10.1093/jnci/djv346. Print 2016 Feb.


Background: PTEN is a tumor suppressor frequently deleted in prostate cancer that may be a useful prognostic biomarker. However, the association of PTEN loss with lethal disease has not been tested in a large, predominantly surgically treated cohort.

Methods: In the Health Professionals Follow-up Study and Physicians' Health Study, we followed 1044 incident prostate cancer cases diagnosed between 1986 and 2009 for cancer-specific and all-cause mortality. A genetically validated PTEN immunohistochemistry (IHC) assay was performed on tissue microarrays (TMAs). TMPRSS2:ERG status was previously assessed in a subset of cases by a genetically validated IHC assay for ERG. Cox proportional hazards models adjusting for age and body mass index at diagnosis, Gleason grade, and clinical or pathologic TNM stage were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association with lethal disease. All statistical tests were two-sided.

Results: On average, men were followed 11.7 years, during which there were 81 lethal events. Sixteen percent of cases had complete PTEN loss in all TMA cores and 9% had heterogeneous PTEN loss across cores. After adjustment for clinical-pathologic variables, complete PTEN loss was associated with lethal progression (HR = 1.8, 95% CI = 1.2 to 2.9). The association of PTEN loss (complete or heterogeneous) with lethal progression was only among men with ERG-negative (HR = 3.1, 95% CI = 1.7 to 5.7) but not ERG-positive (HR = 1.2, 95% CI = 0.7 to 2.2) tumors.

Conclusions: PTEN loss is independently associated with increased risk of lethal progression, particularly in the ERG fusion-negative subgroup. These validated and inexpensive IHC assays may be useful for risk stratification in prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Aged
  • Biomarkers, Tumor / analysis*
  • Body Mass Index
  • Disease Progression
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic
  • Health Personnel / statistics & numerical data
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Male
  • Neoplasm Grading
  • Neoplasm Staging
  • Odds Ratio
  • Oncogene Proteins, Fusion / analysis*
  • PTEN Phosphohydrolase / analysis*
  • Physicians / statistics & numerical data
  • Proportional Hazards Models
  • Prospective Studies
  • Prostatic Neoplasms / chemistry
  • Prostatic Neoplasms / mortality*
  • Prostatic Neoplasms / pathology*
  • Prostatic Neoplasms / surgery
  • Risk Assessment
  • Serine Endopeptidases / analysis*
  • Trans-Activators / analysis*
  • Transcriptional Regulator ERG
  • Tumor Suppressor Proteins / analysis*
  • United States / epidemiology


  • Biomarkers, Tumor
  • ERG protein, human
  • Oncogene Proteins, Fusion
  • Trans-Activators
  • Transcriptional Regulator ERG
  • Tumor Suppressor Proteins
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Serine Endopeptidases
  • TMPRSS2 protein, human