TY - JOUR
T1 - Fluorescence in situ hybridization study shows association of PTEN deletion with ERG rearrangement during prostate cancer progression
AU - Han, Bo
AU - Mehra, Rohit
AU - Lonigro, Robert J.
AU - Wang, Lei
AU - Suleman, Khalid
AU - Menon, Anjana
AU - Palanisamy, Nallasivam
AU - Tomlins, Scott A.
AU - Chinnaiyan, Arul M.
AU - Shah, Rajal B.
N1 - Funding Information:
We thank Jill Granger for editorial review of this paper. Supported in part by the Department of Defense (PC040517, W81XWH-06-1-0224), the National Institutes of Health (Prostate SPORE P50CA69568, R01 CA102872), the Early Detection Research Network (UO1 CA111275-01), the Prostate Cancer Research Foundation and a sponsored research agreement from Gen-Probe Inc. AMC is supported by a Clinical Translational Research Award from the Burroughs Welcome Foundation. SAT is a Fellow of the Medical Scientist Training
Funding Information:
A total of six TMAs were interrogated in this study that represents: (1) 281 clinically localized prostate cancer patients who underwent radical prostatectomy as a monotherapy between 1995– 1996 and 2004–2006 at the University of Michigan Hospital; (2) 47 androgen-independent metastatic prostate cancer patients with multiple metastatic sites and tumors in the prostate (when present) from a rapid autopsy program described earlier12 and (3) 20 benign prostate hyperplasia, 18 atrophy and 35 benign prostate tissues derived from the peripheral zone of prostate containing cancer. Morphology was confirmed by three pathologists (BH, RBS and RM), and three cores (0.6 mm in diameter) were taken from each representative area of interest. Patient demographics of localized prostate cancer are shown in Supplementary Table 1. The detailed clinical, pathological and TMA data were maintained on a secure relational database as described earlier.11 This study was approved by the Institutional Review Board at the University of Michigan Medical School and all the patients provided written informed consent. Both radical prostatectomy series and the rapid autopsy program were part of the University of Michigan Prostate Cancer Specialized Program of Research Excellence Tissue Core.
PY - 2009/8
Y1 - 2009/8
N2 - The link between ERG rearrangement and PTEN (phosphatase and tensin homolog deleted on chromosome 10) deletion is unclear in prostate cancer progression. Using fluorescence in situ hybridization, we systematically validated the frequency and distribution of ERG and PTEN aberrations 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, ERG rearrangement was present in 15% (5/33) of HGPIN, 45% (121/267) of localized cancers and 35% (15/43) of metastases. By contrast, PTEN deletion 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 ERG rearrangement and PTEN deletion was observed in a subset of HGPIN. Significantly, association between PTEN deletion and ERG rearrangement was present both in localized cancers (P0.0008) and metastases (P0.02). Further, immunohistochemistry revealed significant correlation of decreased PTEN protein expression with PTEN genomic deletion both in localized and metastatic cancer. Of note, ERG aberration, but not PTEN deletion, was consistently identical both in localized cancer and adjacent HGPIN. Similarly, whereas all metastases (41/41, 100%) shared the same ERG status across multiple sites from the same patient, 5% (2/41) of cases showed discordance for PTEN deletion status across multiple sites. Collectively, our data support PTEN deletion as a late genetic event in human prostate cancer, presumably a second hit after ERG rearrangement. PTEN deletion and ERG rearrangement may cooperate, but contribute at different stages, in prostate cancer progression.
AB - The link between ERG rearrangement and PTEN (phosphatase and tensin homolog deleted on chromosome 10) deletion is unclear in prostate cancer progression. Using fluorescence in situ hybridization, we systematically validated the frequency and distribution of ERG and PTEN aberrations 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, ERG rearrangement was present in 15% (5/33) of HGPIN, 45% (121/267) of localized cancers and 35% (15/43) of metastases. By contrast, PTEN deletion 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 ERG rearrangement and PTEN deletion was observed in a subset of HGPIN. Significantly, association between PTEN deletion and ERG rearrangement was present both in localized cancers (P0.0008) and metastases (P0.02). Further, immunohistochemistry revealed significant correlation of decreased PTEN protein expression with PTEN genomic deletion both in localized and metastatic cancer. Of note, ERG aberration, but not PTEN deletion, was consistently identical both in localized cancer and adjacent HGPIN. Similarly, whereas all metastases (41/41, 100%) shared the same ERG status across multiple sites from the same patient, 5% (2/41) of cases showed discordance for PTEN deletion status across multiple sites. Collectively, our data support PTEN deletion as a late genetic event in human prostate cancer, presumably a second hit after ERG rearrangement. PTEN deletion and ERG rearrangement may cooperate, but contribute at different stages, in prostate cancer progression.
KW - Deletion
KW - ERG
KW - Fluorescence in situ hybridization
KW - PTEN
KW - Prostate cancer
KW - Rearrangement
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U2 - 10.1038/modpathol.2009.69
DO - 10.1038/modpathol.2009.69
M3 - Article
C2 - 19407851
AN - SCOPUS:68249083702
SN - 0893-3952
VL - 22
SP - 1083
EP - 1093
JO - Modern Pathology
JF - Modern Pathology
IS - 8
ER -