A multicenter study shows PTEN deletion is strongly associated with seminal vesicle involvement and extracapsular extension in localized prostate cancer

Abstract

BACKGROUNDLoss of the phosphatase and tensin homolog (PTEN) tumor suppressor gene is a promising marker of aggressive prostate cancer. Active surveillance and watchful waiting are increasingly recommended to patients with small tumors felt to be low risk, highlighting the difficulties of Gleason scoring in this setting. There is an urgent need for predictive biomarkers that can be rapidly deployed to aid in clinical decision-making. Our objectives were to assess the incidence and ability of PTEN alterations to predict aggressive disease in a multicenter study.METHODSWe used recently developed probes optimized for sensitivity and specificity in a four-color FISH deletion assay to study the Canary Retrospective multicenter Prostate Cancer Tissue Microarray (TMA). This TMA was constructed specifically for biomarker validation from radical prostatectomy specimens, and is accompanied by detailed clinical information with long-term follow-up.RESULTSIn 612 prostate cancers, the overall rate of PTEN deletion was 112 (18.3%). Hemizygous PTEN losses were present in 55/612 (9.0%) of cancers, whereas homozygous PTEN deletion was observed in 57/612 (9.3%) of tumors. Significant associations were found between PTEN status and pathologic stage (P < 0.0001), seminal vesicle invasion (P = 0.0008), extracapsular extension (P < 0.0001), and Gleason score (P = 0.0002). In logistic regression analysis of clinical and pathological variables, PTEN deletion was significantly associated with extracapsular extension, seminal vesicle involvement, and higher Gleason score. In the 406 patients in which clinical information was available, PTEN homozygous (P = 0.009) deletion was associated with worse post-operative recurrence-free survival (number of events = 189), pre-operative prostate specific antigen (PSA) (P < 0.001), and pathologic stage (P = 0.03).CONCLUSIONPTEN status assessed by FISH is an independent predictor for recurrence-free survival in multivariate models, as were seminal vesicle invasion, extracapsular extension, and Gleason score, and preoperative PSA. Furthermore, these data demonstrate that the assay can be readily introduced at first diagnosis in a cost effective manner analogous to the use of FISH for analysis of HER2/neu status in breast cancer. Combined with published research beginning 17 years ago, both the data and tools now exist to implement a PTEN assay in the clinic. Prostate 75: 1206–1215, 2015. © 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc.

PTEN Loss as Determined by Clinical-grade Immunohistochemistry Assay Is Associated with Worse Recurrence-free Survival in Prostate Cancer

“…The original assay involved manual staining of slides, but we have now adapted this assay for automated performance on a Ventana autostainer system and demonstrated equivalence to the manual assay. In a subset of 551 tumors for which IHC (by the automated assay) and FISH data were available [22], we found that intact PTEN immunostaining was 91% specific for the absence of PTEN gene deletion by FISH, and 98% and 62% sensitive for detection of homozygous and hemizygous gene deletion, respectively, by FISH [37]. …”

“…Since the PTEN gene is almost always lost by deletion in PCa, fluorescence in situ hybridization (FISH) has traditionally been used to detect PTEN loss and examine its association with outcomes [13,14,16,17,21,22]. However, we and others have demonstrated that PTEN loss is commonly subclonal and heterogeneous in primary prostate tumors [23–25], making its detection by FISH or techniques that require nucleic acid extraction technically challenging in some cases.…”

PTEN and ERG Molecular Networks in Prostate Cancer

“…The complete PTEN loss in paraffin embedded PCa specimens in patients with primary PCa was also found to correlate significantly with the presence of high stage disease (T3b-T4) as well as with a Gleason score ≥ 7 [14]. Moreover, as far as it concerns oncologic results after radical prostatectomy, in a multicenter study by Troyer et al PTEN deletion status showed a highly significant correlation with pathologic stage and was also correlated strongly with seminal vesicle invasion, extracapsular extension and higher Gleason scores [15]. In a study by Zu et …”

Prognostic Role of PTEN Gene Expression and Length of Survival of Breast Cancer Patients in the North East of Iran

“…The PTEN gene product plays a role in the generation of chemotaxis signals and inhibition of cell proliferation. PTEN deletion can increase progression of prostate carcinoma in mice and human (Wang et al, 2003;Dean et al, 2014;Troyer et al, 2015). In the research conducted by Wan et al, it was indicated that PTEN gene regulates numerous cellular responses on tumour cell chemotaxis.…”

“…Moreover, in vitro studies have indicated that the injection of PTEN to mice lacking the gene can reduce metastasis of cancer cells to the lung (Wan et al, 2007). Not only is the dysfunction of PTEN gene associated with several cancers, but also it can lead to cardiovascular diseases, diabetes, Parkinson's disease and schizophrenia (Gori et al, 2009 its mutation is associated with the rapid metastasis and increased tumour invasive power in some tumours (Sakr et al, 2010;Yang et al, 2010;Okutur et al, 2015;Troyer et al, 2015). However, there is a controversy about PTEN role in different cancers.…”