Fluorescence in situhybridization study shows association of PTENdeletion with ERGrearrangement during prostate cancer progression

The link between ERGrearrangement and PTEN(phosphatase and tensin homolog deleted on chromosome 10) deletion is unclear in prostate cancer progression. Using fluorescence in situhybridization, we systematically validated the frequency and distribution of ERGand PTENaberrations in a cohort of 73 benign prostate tissues, 59 high-grade prostatic intraepithelial neoplasia (HGPIN) foci, 281 localized prostate cancer and 47 androgen-independent metastatic prostate cancer patients. Overall, ERGrearrangement was present in 15% (5/33) of HGPIN, 45% (121/267) of localized cancers and 35% (15/43) of metastases. By contrast, PTENdeletion was identified in 9% (3/33) of HGPIN, 17% (42/251) of localized cancers and 54% (22/41) of metastases, of which 0%, 40% (17/42) and 45% (10/22) were homozygous, respectively. Concomitance of ERGrearrangement and PTENdeletion was observed in a subset of HGPIN. Significantly, association between PTENdeletion and ERGrearrangement was present both in localized cancers (P=0.0008) and metastases (P=0.02). Further, immunohistochemistry revealed significant correlation of decreased PTEN protein expression with PTENgenomic deletion both in localized and metastatic cancer. Of note, ERGaberration, but not PTENdeletion, was consistently identical both in localized cancer and adjacent HGPIN. Similarly, whereas all metastases (41/41, 100%) shared the same ERGstatus across multiple sites from the same patient, 5% (2/41) of cases showed discordance for PTENdeletion status across multiple sites. Collectively, our data support PTENdeletion as a late genetic event in human prostate cancer, presumably a ‘second hit’ after ERGrearrangement. PTENdeletion and ERGrearrangement may cooperate, but contribute at different stages, in prostate cancer progression.