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

Abstract

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.

Figure 1.

PTEN immunostaining of prostate cancer tissue microarray (TMA) cores. A) PTEN is intact in small infiltrating cancer glands (arrowheads), with similar cytoplasmic staining intensity (brown pigment) as seen in adjacent larger benign glands (arrow). B) PTEN is homogeneously lost in small infiltrating tumor glands (arrowheads), compared with larger benign glands (arrow) where PTEN is intact. Note intraductal spread of prostate cancer cells with PTEN loss within the larger benign gland (arrow). C) Heterogeneous PTEN loss in tumor sampled on a single TMA core with some cancer glands showing intact PTEN (arrowhead) and others showing PTEN loss (arrow).

Figure 2.

Kaplan-Meier survival plot for association of interaction of PTEN and ERG status with lethal prostate cancer among men diagnosed with prostate cancer between 1983 and 2009 within the Health Professional Follow-up Study and the Physicians’ Health Study. PTEN intact / ERG negative   ——————— PTEN intact / ERG positive   – – – – – – – – – – Any PTEN loss / ERG positive  — — — — — — Any PTEN loss / ERG negative  — . — . — . — .