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A Prospective Investigation of PTEN Loss and ERG Expression in Lethal Prostate Cancer
Thomas U Ahearn1, Andreas Pettersson2, Ericka M Ebot2
1Department of Epidemiology (TUA, AP, EME, TG, REG, KMW, JRR, HDS, ELG, MJS, LAM) and Department of Nutrition (ELG, MJS), Harvard T. H. Chan School of Public Health, Boston, MA; Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden (AP); Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA (REG); Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD (CLM, JLH, AMDM, TLL); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (JRR, ELG, MJS, LAM, KMW); Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital, Boston, MA (HDS); Pathology Unit, Addarii Institute, S. Orsola-Malpighi Hospital, Bologna, Italy (MF); Department of Histopathology Research, Trinity College, Dublin, Ireland (RF, SF); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA (ML); Department of Oncology (AMDM, TLL) and Department of Urology (ADMD), Johns Hopkins University School of Medicine, Baltimore, MD. tahearn@hsph.harvard.edu.
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.
