Loss of PTEN Is Associated with Aggressive Behavior in ERG-Positive Prostate Cancer

• Published in: Cancer epidemiology, biomarkers & prevention Vol. 22; no. 12; pp. 2333 - 2344
• Main Authors: Leinonen, Katri A., Saramäki, Outi R., Furusato, Bungo, Kimura, Takahiro, Takahashi, Hiroyuki, Egawa, Shin, Suzuki, Hiroyoshi, Keiger, Kerri, Ho Hahm, Sung, Isaacs, William B., Tolonen, Teemu T., Stenman, Ulf-Håkan, Tammela, Teuvo L.J., Nykter, Matti, Bova, G. Steven, Visakorpi, Tapio
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.12.2013
• Subjects: Biological and medical sciences; Biomarkers, Tumor - metabolism; Cohort Studies; Disease-Free Survival; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Male; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Metastasis; Nephrology. Urinary tract diseases; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Paraffin Embedding; Prostatectomy; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Prostatic Neoplasms - surgery; Prostatic Neoplasms, Castration-Resistant - enzymology; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - pathology; Prostatic Neoplasms, Castration-Resistant - surgery; PTEN Phosphohydrolase - deficiency; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Trans-Activators - biosynthesis; Trans-Activators - genetics; Trans-Activators - metabolism; Transcriptional Regulator ERG; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Urinary system disease; Prostate disease; Loss; Malignant tumor; Association; Cancerology; C-Onc gene; PTEN Gene; Behavior; Male genital diseases; Prostate cancer; Protooncogene; Cancer; Tumor suppressor gene; High malignancy
• ISSN: 1055-9965; 1538-7755; 1538-7755
• DOI: 10.1158/1055-9965.EPI-13-0333-T

Background: The associations of ERG overexpression with clinical behavior and molecular pathways of prostate cancer are incompletely known. We assessed the association of ERG expression with AR, PTEN, SPINK1, Ki-67, and EZH2 expression levels, deletion, and mutations of chromosomal region 3p14 and TP53, and clinicopathologic variables. Methods: The material consisted of 326 prostatectomies, 166 needle biopsies from men treated primarily with endocrine therapy, 177 transurethral resections of castration-resistant prostate cancers (CRPC), and 114 CRPC metastases obtained from 32 men. Immunohistochemistry, FISH, and sequencing was used for the measurements. Results: ERG expression was found in about 45% of all patient cohorts. In a multivariate analysis, ERG expression showed independent value of favorable prognosis (P = 0.019). ERG positivity was significantly associated with loss of PTEN expression in prostatectomy (P = 0.0348), and locally recurrent CRPCs (P = 0.0042). Loss of PTEN expression was associated (P = 0.0085) with shorter progression-free survival in ERG-positive, but not in negative cases. When metastases in each subject were compared, consistent ERG, PTEN, and AR expression as well as TP53 mutations were found in a majority of subjects. Conclusions: A similar frequency of ERG positivity from early to late stage of the disease suggests lack of selection of ERG expression during disease progression. The prognostic significance of PTEN loss solely in ERG-positive cases indicates interaction of these pathways. The finding of consistent genetic alterations in different metastases suggests that the major genetic alterations take place in the primary tumor. Impact: Interaction of PTEN and ERG pathways warrants further studies. Cancer Epidemiol Biomarkers Prev; 22(12); 2333–44. ©2013 AACR.