Determination of Intratumoral Heterogeneity for PTEN Loss in Prostate Cancer by IHC for PTEN and ERG
Berrak Gumuskaya Ocal, Bora Gurel, Jessica L Hicks, Tamara Lotan, Angelo M De Marzo. Johns Hopkins, Baltimore, MD
Background: The determination of tumor heterogeneity for key oncogenic factors is important for understanding multi-step tumor progression. ERG rearrangements and PTEN loss are two of the most common genetic alterations in prostate cancer. Heterogeneity of PTEN loss has been shown to be common (∼46%) in primary prostate cancer, even within tumor foci with homogeneous ERG rearrangements as assessed by FISH (BJUI 107:477-, 2011), suggesting that PTEN loss gennerally occurs after ETS family member rearrangements. Yet, the determination of ERG and PTEN status using interphase FISH assays is cumbersome. ERG protein overexpression, as assessed by IHC, is highly associated with ERG gene rearrangement in prostate cancer. We have recently validated an IHC assay to detect PTEN protein loss in tissue samples that is highly sensitive for detecting either heterozygous and homozygous PTEN deletions as assessed by genomic means (Lotan et al., Clin Cancer Res. 2011 Aug 30). We used IHC to determine ERG and PTEN status to calculate the fraction of cases with homogeneous/heterogeneous ERG and PTEN staining in a given tumor.
Design: Using a single standard tissue section from the index tumor from radical prostatectomies (N= 68), enriched for relatively high grade (53% Gleason 7, 21% Gleason 8-9) and stage tumors, we examined ERG (Biocare Medical) and PTEN (Cell signaling) status by IHC. IHC for ERG was categorized as positive or negative in a given tumor focus. PTEN loss was assessed as a dichotomous variable as either present or markedly decreased/absent. We determined whether ERG or PTEN staining was homogeneous or heterogeneous in a given tumor.
Results: 59% (N=40) of cases showed ERG positivity, with 7% of these (N=3/40) cases showing intratumoral ERG heterogeneity. 63% (N=43/68) of cases showed PTEN loss, and of these, 67% (N=29/43) showed heterogeneous loss. In ERG homogeneously positive cases, any PTEN loss occurred in 70% (N=26/37) of cases, and of these, 65% (N=17/26) showed heterogeneous loss. In ERG negative tumors, 58% (N=16/28) showed PTEN loss, and of these, 69% (N=11/16) showed heterogeneous PTEN loss. ERG expression did not correlate with Gleason score or stage, while any PTEN loss correlated with increased Gleason score (P=0.017) and pathological stage (P<0.001).
Conclusions: These results support the concept that in most cases of PTEN loss, the loss commenses as a subclonal event within an established prostatic carcinoma clone. The combination of ERG and PTEN IHC staining can be used as a simple test to acertain PTEN status within a given prostate cancer in either a research or clinical setting.
Category: Genitourinary (including renal tumors)
Monday, March 19, 2012 1:00 PM
Poster Session II # 165, Monday Afternoon