PTEN Immunoexpression Research Articles

Immunohistochemical expression of PTEN (phosphatase and tension homolog) in endometrial carcinoma

Background and objective: Different molecular alterations have been described in the pathogenesis of endometrial carcinoma, among themis mutation of the PTEN (phosphatase and tension homolog), a tumor suppressor gene. This study aimed to detect PTEN immunoexpression in endometrial carcinoma and to asses the association between PTEN immunoexpression with the clinicopathological parameters. Methods: This cross-sectional retrospective study was carried out between January 2016-December 2021 in Erbil city. A total of 112 formalin fixed, paraffin embedded, archival tissue blocks of total abdominal hysterectomy samples were collected in Erbilcity. The clinicopathological characteristics of the tumors were revised, and the specimens were analyzed immunohistochemically using monoclonal PTEN antibody clone 6H2.1 (Dako. Results: Seventy- seven cases (68.8%) were labeled as negative for PTEN immunoexpression. While 35 cases (31.2%) were labeled as positive for PTEN immunoexpression. PTEN immunoexpression was significantly associated with the tumor histological types (P = 0.001), while no significant association was found between PTEN immunoexpression and other clinicopathological parameters. Conclusion: Loss of PTEN immunoexpression frequently seen in endometrioid type of endometrial carcinoma than other types of endometrial carcinoma and is significantly associated with the histological types of endometrial carcinoma.

PTEN Immunoexpression in Atypical Endometrial Hyperplasia and Endometrioid Endometrial Carcinoma: A Research Protocol

Introduction: One of the major cancers affecting women is of Endometrial Carcinoma (EC). Therefore, its molecular characterisation remains important. Phosphatase and Tensin Homolog (PTEN) gene defects are one such molecular pathology commonly seen in lesion of atypical endometrial hyperplasia and EC. However, studies on PTEN immunoexpression in India are scarce. Aim: To study immunoexpression of PTEN and its correlation with various clinicopathologic parameters in lesion of atypical endometrial hyperplasia and EC. Materials and Methods: It will be carried out as a crosssectional study with prospective and retrospective design with sample size of 20 cases each in two groups- cases diagnosed on biopsy or surgical specimen of atypical endometrial hyperplasia and endometrioid endometrial carcinoma type -1, dividing them into sample size of 20 for each group. PTEN immunoexpression will be observed by immunohistochemical method on paraffin section of the tissue. The study would make the observation on the PTEN positivity by IHC in atypical endometrial hyperplasia and type-1 EC. The positive research of IHC will be compared for various other clinicopathologic parameters included in the study for both the endometrial lesion. The statistics of comparison will be drawn by using standard statistical test.

PTEN Immunohistochemistry.

Intestinal neuronal dysplasia type B (IND B) is a complex entity involving the enteric nervous system, clinically manifested with constipation in infancy. Diagnosis has been established by histopathologic analysis of rectal biopsies. However, the criteria for the diagnosis have been questioned and modified, hindering diagnostic practice. To analyze the applicability of PTEN immunohistochemistry in the diagnosis of IND B and to compare with control cases and cases of Hirschsprung disease (HD). PTEN immunohistochemical expression was analyzed in colorectal samples from 29 cases of IND B and compared with 4 control cases and 6 cases of HD. The pattern of PTEN immunoexpression was analyzed in glial cells of the submucosal and myenteric nerve plexuses and in neural fibrils of the muscularis propria using a scoring system. Marked reduction or absence of PTEN expression was observed in glial cells of the submucosal nerve plexuses in all cases of the IND B group and in the myenteric nerve plexuses in 28 of 29 cases (96.5%). Lack of PTEN expression was detected in neural fibrils within the muscularis propria in 21 of 29 cases (72%) of the IND B group. PTEN expression was positive in the same neural structures of the control and HD groups. PTEN immunohistochemistry may be a valuable tool in the diagnostic evaluation of IND B. Lack of or reduction of PTEN expression in neural fibrils within the muscularis propria suggests that involvement of the neuromuscular junction may be a key event in the pathogenesis of the motility disturbance occurring in IND B.

Immunoexpression of PTEN, HER2/neu, and Ki-67 in endoscopic gastric carcinoma biopsies; their correlation with histological subtypes and one-year survival.

Gastric carcinoma is a major cause of cancer-related morbidity and mortality worldwide. Gastric neoplasms arise from genetic and epigenetic changes in various genes. Present study evaluates the immunoexpression of PTEN, HER2/neu, and Ki-67 in endoscopic gastric carcinoma biopsies and correlates the expression of these proteins with clinicopathological features. Adequate endoscopic biopsies of 27 cases of gastric carcinoma were evaluated for World Health Organization (WHO) and Lauren's classification subtypes along with HER2/neu, PTEN, and Ki-67 immunoexpression. HER2/neu immunostaining was scored as proposed in the Trastuzumab for gastric cancer (ToGA) trial while PTEN staining and downregulation were assessed using an immunoreactive score. The cut-off for Ki-67 expression was taken as 90th percentile of the values in adjacent non-neoplastic tissue. All statistical analysis was done at 5% level of significance with SPSS v22 statistical software. Tubular adenocarcinoma was the commonest WHO histological subtype and 56% of cases were of intestinal type as per Lauren's classification. 55.6% of cases showed a complete loss of PTEN expression in neoplastic tissue. 17 of the 19 cases with adjacent non-neoplastic tissue showed PTEN downregulation in neoplastic tissue. 81.5% of cases had a high Ki-67 index and HER2/neu overexpression was noted in 36% of cases. All the four cases who died had high Ki-67 proliferation indices; 3 patients had loss of PTEN expression and HER2/neu overexpression. We conclude that these immunomarkers can play important role in the behavior of gastric carcinomas and can be targeted for new therapies.

Does obesity modify the expression of cyclin D1 and pten in endometrial polyps in postmenopausal women?

Objective To assess cyclin D1 and PTEN immunoexpression in benign endometrial polyps (EPs) in asymptomatic postmenopausal women and its correlation with obesity. Methods: This was a cross-sectional study based on data from a sample of 52 patients diagnosed with EP between February 2018 and January 2019. The women included in this study were amenorrheal for at least 1 year and were asymptomatic (no postmenopausal bleeding). Obesity defined by body mass index (BMI) was investigated for correlation with Cyclin-D1 and PTEN gene expression (immunohistochemistry) in glandular and stromal compartments of polyps. Results: No significant differences among groups were identified in any clinical and epidemiological parameter (age, age of menopause, time since menopause, number of gestations, polyp size, leucocyte count, fasting blood glucose and basic pathologies), except for BMI. Body mass index did not alter PTEN or Cyclin D1 immunoexpression. Conclusion: Our study shows that obesity does not appear to be a relevant factor in the immunoexpression of PTEN and Cyclin D1 in benign EP, in either the stromal or glandular compartments.

Role of phosphatase and tensin homolog in pathogenesis of ameloblastoma: An immunohistochemical study.

Altered molecular signaling pathways in ameloblastoma have been identified to play a pivotal role in the mechanism of oncogenesis, differentiation, and tumor progression. Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway is one of the signaling pathways that are associated with the pathogenesis of ameloblastoma. Phosphatase and tensin homolog (PTEN) controls cell migration and proliferation. It monitors the level of the Akt and maintains cellular integrity. The present study was aimed to study the immunoexpression of PTEN in ameloblastoma to understand its role in the pathogenesis of ameloblastoma. Twenty cases of ameloblastoma and ten cases of normal tooth germ were subjected to immunohistochemical staining against PTEN. Strong PTEN immunopositivity was seen in the tooth germs, while weak positivity was seen in the ameloblastoma. The immunoscore for PTEN was calculated by adding the percentage score and the intensity score. Seventeen cases showed the reduced PTEN expression in the epithelial component of ameloblastoma. The unpaired t-test showed a statistically significant difference in the mean PTEN immunoscore in tooth germ and ameloblastoma. The study showed reduced PTEN immunoreactivity, which plays a role in the pathogenesis of ameloblastoma, through Akt pathway.

IMMUNOEXPRESSION PTEN IN ORAL EPITHELIAL DYSPLASIAS AND SQUAMOUS CELL CARCINOMA

Epithelial oral dysplasia (OED) is a risk factor for developing subsequent oral squamous cell carcinomas (OSCC). PTEN is a tumor suppressor gene of the PI3K/AKT pathway, which is 1 of the most deregulated pathways in cancer. Objective: To perform immunohistochemical analysis of PTEN in OED and OSCC samples with different histologic gradations of malignancy. Study Design: Formalin-fixed paraffin-embedded samples of 19 OED and 16 OSCC were included to immunohistochemistry analysis of PTEN (Abcam, clone 31392, 1:400, overnight). Quantitative and qualitative evaluation of PTEN immunostaining in 5 fields at 400 x magnification was performed, correlating PTEN immunoexpression in different degrees of DEO and histologic stages of CEO. Results: The PTEN immunostaining pattern showed both homogeneous and heterogeneous in samples of OSCCs and OEDs. The average number of cells with nuclear immunostaining was significantly higher in OSCCs compared to OEDs and control (P Conclusions: The heterogeneity of PTEN protein expression in OED and OSCC samples was demonstrated. Immunoexpression of PTEN was higher in OSCC and severe and moderate dysplasia compared to the control and mild OED, which suggested the functional inactivation of PTEN in this cancer. This work was supported by grants from Conselho Nacional Desenvolvimento Cientifico e Tecnologico (CNPq).

Loss of heterozygosity and immunoexpression of PTEN in oral epithelial dysplasia and squamous cell carcinoma

IntroductionOral epithelial dysplasia (OED) is a risk factor for developing subsequent oral squamous cell carcinoma (OSCC). Loss of heterozygosity (LOH) profiles have been validated as risk predictors of malignant transformation of OED. It is still unclear if Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) allelic loss also occurs in initial stage malignant lesions and if the allelic loss is involved as one of the mechanisms of oral carcinogenesis. Thus, this study objective investigate LOH of PTEN gene and the immunohistochemical expression of the protein in OED and OSCC samples. Material and methodsFormalin-fixed paraffin-embedded samples of 19 OEDs and 16 OSCCs were included to immunohistochemistry and LOH analysis. Two polymorphic microsatellite markers (AFMA086WG9 and D10S1765) located in chromosome 10 were used in this study for LOH analysis. For immunohistochemical analysis, 5 random fields with 400× magnification were evaluated quantitatively and qualitatively in epithelial and neoplastic cells. ResultsAFMA086WG9 marker only demonstrated LOH in OEDs cases (10.5%). D10S1765 marker demonstrated LOH in 57.2% of OEDs and 50% of OSCCs. Higher nuclear immunostaining was detected in cases of OSCCs when compared to OEDs (p < .001) and there was strong cytoplasmic immunoexpression in OSCCs (p < .045). ConclusionsWe provide evidence that the allelic loss of PTEN is present in premalignant oral lesions and OSCCs, however the LOH of PTEN does not seems to influence its protein expression.

Concomitant p53 and PTEN immunoexpression to predict the risk of malignancy in endometrial polyps

The aim of this retrospective cross-sectional study was to assess the usefulness of phosphase and tensin homolog deleted on chromosome 10 (PTEN) and p53 protein immunoexpression in predicting the risk of malignancy in endometrial polyps. The study was conducted at tertiary public hospital, university teaching center, and private practice clinic.A total of 159 patients with endometrial polyps who underwent hysteroscopic polypectomy between January 2010 to December 2014 were included. p53 and PTEN immunoexpression were assessed in histologic endometrial polyp samples. Patients were allocated into 2 groups: group A, endometrial polyps without atypia (120), and group B, endometrial polyps with atypia (39), which were subdivided into A1 (80) and B1 (21) = p53−/PTEN+ immunostaining; A2 (20) and B2 (11) = p53+/PTEN+; A3 (14) and B3 (4) = p53+/PTEN−; A4 (6) and B4 (3) = p53−/PTEN−.There was no significant difference between groups regarding clinical and epidemiologic parameters, except for age. Neoplasia incidence within groups was higher when at least 1 marker was abnormally stained (in group A, P = .0089, odds ratio [OR] = 13.94 [1.62; 120.27]; in group B, P = .0255, OR 12.73 [1.38; 117.27]). Overall neoplasia incidence was higher in group B than in group A (20.5% vs 5.8%; P = .0113). Malignant neoplasia was found more frequently in patients with p53+ (P = .0006, OR = 7.67 [2.30; 25.54]) and PTEN− (P = .0043; OR = 5.43 [1.77; 16.61]).Immunohistochemical analysis using p53 and PTEN as markers, either alone or concomitantly, can be useful to predict malignant transformation in cases of endometrial polyps.

Immunoexpression of Pten in Oral Epithelial Dysplasias

To evaluate the immunostaining for PTEN protein in oral epithelial dysplasias (OEDs) and relate it with the histological grade using the binary system.

Loss of PP2A and PTEN immunoexpression coexists with survivin overexpression in adenomyosis

Phosphatase and tensin homolog (PTEN) and protein phosphatase type 2A (PP2A) are negative modulators of PI3K/AKT/survivin signaling. To evaluate immunoexpression of PTEN, PP2A and survivin in adenomyosis, ectopic lesions from 28 patients with adenomyosis and endometria from 30 controls without adenomyosis were employed in the study. The expression of PTEN, PP2A and survivin was examined with the use of immunohistochemistry. We found a decreased expression of PP2A and PTEN in adenomyosis. The expression of PTEN showed great individual differences in adenomyosis, although expression of both PP2A and PTEN was lower in adenomyosis than in normal endometria. In contrast, the expression of survivin was higher in adenomyosis. Our results suggest the important role of the PI3K cascade in the pathogenesis and development of adenomyosis.

Dysregulation of the mammalian target of rapamycin pathway in chromophobe renal cell carcinomas

Targeted therapy in advanced clear cell renal cell carcinomas (RCC) is now an established modality. The latter is in stark contrast to non-clear cell subtypes. We explored the translational support for the use of antagonists of the mammalian target of rapamycin (mTOR) and the vascular endothelial growth factor pathways in chromophobe RCC. The immunoexpression of PTEN, phos-AKT, phosphorylated S6 (phos-S6), 4EBP1, p27, c-MYC, and HIF-1α was evaluated in 33 patients with chromophobe RCC who were treated by partial/radical nephrectomy without adjuvant therapy. PTEN was lower in tumor than in normal kidney (P<.001), and loss of PTEN expression was found in 67% of the tumors. In tumor tissues, phos-S6 and 4EBP1 were higher than in normal kidney (P≤.005). Conversely, scores of p27 were lower in tumor than in normal kidney (P<.001). Finally, scores of phos-AKT, c-MYC, and HIF-1α were not significantly different in tumor and in normal kidney. Overall mortality and cancer-specific mortality were 9% and 0%, respectively. Multifocal tumors had higher levels of PTEN, phos-AKT, and HIF-1α (P≤.01). None of the clinicopathologic variables (age, ethnicity, gender, pT stage, tumor size, multifocality, and positive surgical margins) was associated with outcome. Similarly, none of the tested biomarkers predicted overall mortality, either in unadjusted or adjusted Cox regression models. In summary, our study provides new evidence of dysregulation of the mTOR pathway in chromophobe RCC. Immunohistochemistry for mTOR pathway and hypoxia-induced pathway members lacked prognostic significance in our cohort.

Abstract 317: Role of ATM and PTEN in prostatic carcinogenic dog prostate: validation of aCGH results.

Abstract The canis lupus familiares is the only species besides human that spontaneously develop prostatic carcinoma (PCa). In addition, the metastatic sites are similar to those frequently reported in men. For these reasons, the dog is the best natural model to study the molecular mechanisms in PCa development providing a natural animal model for treatment by molecular targets. Previously, we investigated copy number alterations by arrayCGH (Canine Genome CGH Microarray 4x44K-G2519F, Agilent Technologies) in canine prostatic lesions: 3 benign prostatic hyperplasias (BPH), 4 proliferative inflammatory atrophies (PIA), and 14 PCa. Five histologically normal prostatic tissues were used as reference. Genomic alterations were evaluated using Genomic Workbench Standard Edition 5.0.14. This previous study revealed significant copy number losses of Atm and Pten exclusively in PCa. In the present study, ATM and PTEN immunoexpression were investigated using a tissue microarray (TMA) containing 149 canine prostatic paraffin-embedded lesions (BPH, PIA and PCa) collected from 67 animals. Immunohistochemical reactions were performed using the polyclonal rabbit antibody anti-PTEN (Santa Cruz Biotech, 1:50) and anti-ATM (Abcam, 1:50). The sections were developed with diaminobenzidine (DAB) and peroxidase. The immunohistochemical staining was assessed in each core by the distribution of positive cells for each antibody per lesion (score 1: &amp;lt;25% cells positive, 2: 26% to 50%, 3: being 51% and 75% and 4:&amp;gt; 75%) and intensity (1: weak, 2: moderate, 3: intense). Chi-square or Fisher exact test was used to determine the association between the categorical variables using GraphPad Prism 5 (GraphPad Software Inc., La Jolla, CA). Distribution of positive cells did not differ among lesions. PCa and PIA showed more samples with weak intensity for ATM when compared to normal prostatic tissue and BPH (PCa: p=0,032 and PIA: p=0,025). Benign prostatic hyperplasia and normal samples presented intense PTEN immunostaining than PCa (p=0,021) and PIA (p=0,0013). These results suggest that ATM and PTEN proteins expression in canine prostatic carcinoma are downregulated possibly by copy number losses. These findings are similar from those described in prostate carcinomas from human corroborating for the use of dogs as a natural model to study prostatic disease in men. Citation Format: Carlos E. Fonseca Alves, Patricia R. Pellicciari, Marcela M. P. Rodrigues, Silvia R. Rogatto, Renee L. Amorim. Role of ATM and PTEN in prostatic carcinogenic dog prostate: validation of aCGH results. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 317. doi:10.1158/1538-7445.AM2013-317

Immunoexpression of the PTEN protein and matrix metalloproteinase-2 in endometrial cysts, endometrioid and clear cell ovarian cancer

Endometrioid and clear cell ovarian adenocarcinomas are suspected to derive from ectopic endometrial foci. The aim of the study was to determine PTEN and MMP-2 immunoexpression in endometrial ovarian cysts, endometrioid and clear cell ovarian carcinomas and to assess the relationship between the abovementioned values and clinical data of patients in order to find the marker of increased risk of malignant proliferation based on ovarian endometriotic lesions. Detailed analysis of the collected data was conducted to investigate the correlation between immunohistochemical expression of the examined antigens, histopathological diagnosis and clinical condition of patients. 20 endometrial adenocarcinomas, 21 clear cell ovarian cancers and 26 endometrial cysts were included in the study The control group consisted of 29 specimens of physiological endometrium: 16 samples of the proliferative phase and 13 samples of the secretory phase. Protein expression of PTEN and MMP-2 was evaluated by immunohistochemistry Protein immunoexpression in the collected specimens was estimated with the use of light microscope and MultiScan software. Immunoreactivity of the PTEN antigen was assessed by the quantitative method, whereas MMP-2 immunoexpression was evaluated by the semi-quantitative method. Two-sided tests were used for statistical inference. Generalized linear models were used to compare the studied groups. Error distributions were selected using the Akaike criterion (AIC). Statistical analysis was conducted with the use of the R Statistical Package. MMP-2 immunoreactivity differed significantly between the study groups and controls (p<0.001). PTEN immunoexpression was the strongest in endometrial cysts (53.7 %), lower in clear cell cancers (50.2%) and the lowest in endometrioid adenocarcinomas (43.88%), but the differences were not statistically significant (p=0.17). PTEN reactivity in the group of endometrioid carcinomas was significantly higher (p=0.02), while MMP-2 expression had a falling tendency (p=0.076) in obese women. Increased MMP-2 expression in the successive groups may imply a rising invasive potential of the epithelial cells in endometrial cysts, endometrioid and clear cell adenocarcinomas. Strong immunoreactivity for PTEN in proliferative endometrium implies its role in the regulation of endometrial proliferation. PTEN activity may reduce MMP-2 expression in insulin resistant women suffering from endometrial ovarian cancer Simultaneous evaluation of PTEN and MMP-2 immunoexpression in ectopic endometrial foci cannot be used to identify women with an increased risk of neoplastic transformation.

The impact of PTEN tumor suppressor gene on acquiring resistance to tamoxifen treatment in breast cancer patients

Tamoxifen is a standard therapeutical treatment in patients with estrogen receptor positive breast carcinoma. However, less than 50% of estrogen receptor positive breast cancers do not respond to tamoxifen treatment whereas 40% of tumors that initially respond to treatment develop resistance over time. The underlying mechanisms for tamoxifen resistance are probably multifactorial but remain largely unknown. The primary aim of this study was to investigate the impact of PTEN tumor suppressor gene on acquiring resistance to tamoxifen by analyzing loss of heterozygosity (LOH) and immunohystochemical expression of PTEN in 49 primary breast carcinomas of patients treated with tamoxifen as the only adjuvant therapy. The effect of PTEN inactivation on breast cancer progression and disease outcome was also analyzed. Reduced or completely lost PTEN expression was observed in 55.1% of samples, while 63.3% of samples displayed LOH of PTEN gene. Inactivation of PTEN immunoexpression significantly correlated with the PTEN loss of heterozygosity, suggesting LOH as the most important genetic mechanism for the reduction or complete loss of PTEN expression in primary breast carcinoma. Most importantly, LOH of PTEN and consequential reduction of its immunoexpression showed significant correlation with the recurrence of the disease. Besides, our study revealed that LOH of PTEN tumor suppressor was significantly associated with shorter disease free survival, breast cancer specific survival and overall survival. In summary, our results imply that LOH of PTEN could be used as a good prognostic characteristic for the outcome of breast cancer patients treated with tamoxifen.

IDH1 mutation of gliomas with long-term survival analysis

A recurrent mutation affecting codon 132 of the isocitrate dehydrogenase 1 (IDH1) gene has been found in ~5% of primary glioblastomas (GBMs), but in >70% of secondary GBMs or oligodendroglial and astrocytic tumors. We investigated IDH1 mutations in a series of 134 brain tumors to determine the prevalence and prognostic impact of IDH1 mutations. We also examined the correlations among histology, p53 and PTEN immunoexpression, MGMT methylation status, 1p 19q co-deletion and EGFR gene amplification. The 134 brain tumors included 41 low-grade oligodendrogliomas (LOs), 47 anaplastic oligodendrogliomas (AOs) and 46 primary GBMs. Data showed that 53.7% (72/134) of cases showed mutations affecting codon 132 of IDH1, including 73.2% of LOs, 82.9% of AOs and three primary GBMs (6.5%). All IDH1 mutations were Arg132His. In a survival analysis, patients with IDH1 mutations had better survival compared to those with wild-type IDH1 (p<0.05) in LOs and AOs, but not in primary GBMs (p=0.587). In addition, in patients with both IDH1 mutation and MGMT methylation, p53 overexpression was a significant poor prognostic factor both in LOs and AOs. However, IDH1 mutation was not correlated with common genetic profiles that affect patient prognosis, including MGMT methylation, 1p 19q co-deletion, PTEN loss and EGFR amplification in LOs, AOs and GBMs. From our results, IDH1 mutation was an independent positive prognostic factor in LOs and AOs, especially in the absence of p53 overexpression.

395 DYSREGULATION OF MTOR PATHWAY IN PLASMACYTOID VARIANT OF UROTHELIAL CARCINOMA OF THE URINARY BLADDER

You have accessJournal of UrologyUrothelial Cancer: Natural History & Pathophysiology/Marker1 Apr 2012395 DYSREGULATION OF MTOR PATHWAY IN PLASMACYTOID VARIANT OF UROTHELIAL CARCINOMA OF THE URINARY BLADDER Nilda Gonzalez-Roibon, Alcides Chaux, Adeboye O. Osunkoya, Turki Al-Hussain, Jessica Hicks, Jonathan I. Epstein, and George Netto Nilda Gonzalez-RoibonNilda Gonzalez-Roibon Baltimore, MD More articles by this author , Alcides ChauxAlcides Chaux Baltimore, MD More articles by this author , Adeboye O. OsunkoyaAdeboye O. Osunkoya Atlanta, GA More articles by this author , Turki Al-HussainTurki Al-Hussain Baltimore, MD More articles by this author , Jessica HicksJessica Hicks Baltimore, MD More articles by this author , Jonathan I. EpsteinJonathan I. Epstein Baltimore, MD More articles by this author , and George NettoGeorge Netto Baltimore, MD More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.459AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Mammalian target of rapamycin (mTOR) pathway plays an important role in cell growth, migration, and proliferation. mTOR pathway dysregulation has been linked to oncogenesis in several malignancies, including conventional urothelial carcinoma of bladder. Several antineoplastic agents targeting mTOR pathway are currently available. Plasmacytoid variant of urothelial carcinoma (UC) is a rare but aggressive variant of bladder cancer. The current study assesses mTOR pathway status as well as c-myc and p27 expression, two markers known to interact with this pathway. METHODS Nineteen cases of plasmacytoid UC were retrieved from the surgical pathology files of our 2 institutions, including 12 cases from the consultation service of 2 of the authors. Whole sections were evaluated for immunoexpression of PTEN, phosphorylated mTOR (phos-mTOR), phosphorylated AKT (phos-AKT), phosphorylated S6 (phos-S6), c-myc, and p27. Antibody sources and IHC parameters were as previously described (Cancer 2010;116:5517). Cases with >10% loss of cytoplasmic PTEN expression were considered to show loss of PTEN. For the remaining markers, expression intensity (0 to 3+) and extent (0% to 100%) was evaluated in each tumor. An H-Score (Σintensity × percentage) was calculated. Pairwise correlation coefficients (CC) were estimated to assess relationship among markers expression. RESULTS PTEN loss was encountered in 5 cases (28%) of plasmacytoid UC. In contrast, high levels of phos-mTOR (mean 218, range 97 - 285), phos-AKT (mean 211, range 67 - 295) and phos-S6 (mean 248, range 164 - 298) were found. Low expression of c-myc (mean 51, range 0 - 223) and of p27 (mean 61, range 0 - 225) were noted. phos-AKT expression positively correlated with phos-mTOR (CC = 0.54, P = .02). phos-S6 expression negatively correlated with c-myc expression (CC = -0.67, P < .005). CONCLUSIONS We found dysregulation of the mTOR pathway in plasmacytoid urothelial carcinoma of the urinary bladder. These results suggest that the use of mTOR inhibitors might be beneficial for patients with this aggressive variant of urothelial carcinoma. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e162 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nilda Gonzalez-Roibon Baltimore, MD More articles by this author Alcides Chaux Baltimore, MD More articles by this author Adeboye O. Osunkoya Atlanta, GA More articles by this author Turki Al-Hussain Baltimore, MD More articles by this author Jessica Hicks Baltimore, MD More articles by this author Jonathan I. Epstein Baltimore, MD More articles by this author George Netto Baltimore, MD More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

2128 LOSS OF PTEN EXPRESSION IS AN INDEPENDENT PREDICTOR OF RECURRENCE IN PROSTATE CARCINOMA

You have accessJournal of UrologyProstate Cancer: Markers II1 Apr 20102128 LOSS OF PTEN EXPRESSION IS AN INDEPENDENT PREDICTOR OF RECURRENCE IN PROSTATE CARCINOMA Luciana Schultz, Elizabeth Platz, Antoun Toubaji, Roula Albadine, Jessica Hicks, William Isaacs, Christian McEvoy, Alan Meeker, Angelo De Marzo, and George Netto Luciana SchultzLuciana Schultz More articles by this author , Elizabeth PlatzElizabeth Platz More articles by this author , Antoun ToubajiAntoun Toubaji More articles by this author , Roula AlbadineRoula Albadine More articles by this author , Jessica HicksJessica Hicks More articles by this author , William IsaacsWilliam Isaacs More articles by this author , Christian McEvoyChristian McEvoy More articles by this author , Alan MeekerAlan Meeker More articles by this author , Angelo De MarzoAngelo De Marzo More articles by this author , and George NettoGeorge Netto More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.2216AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate adenocarcinoma (PCa) shows genetic loss or mutation of at least one PTEN allele in approximately 30-70% of cases. PTEN loss is thought to play an early critical role in prostate oncogenesis possibly in cooperation with ERG oncogene activation. In the current study, we investigated the role of loss of PTEN expression in predicting disease recurrence in a well characterized nested case-control cohort of PCa which we have previously assessed for TMPRSS2-ERG fusion status. METHODS The cohort consisted of 8 TMAs containing paired tumor and normal tissues from radical prostatectomies (RRP) performed at our hospital between 1993 and 2001. They included 209 cases (recurred on follow up) and 209 controls (without PCa recurrence) that were tightly matched for Gleason grade, pTNM stage, ethnicity and patient age. Standard immunohistochemistry for PTEN (Cell Signalling) was performed. PTEN expression was assessed as percentage of cells staining (extent) and assigned an incremental (0 to 3+) intensity score. Additionally, an H-score was calculated as the product of intensity x extent. Prognostic interaction between PTEN expression, TMPRSS2-ERG fusion status and Chromosome 21 polyploidy (ERG gene locus) was evaluated. RESULTS Mean length of follow-up was 2.6 and 6.2 years in the case and control groups respectively. PTEN expression decreased with patient age (p=0.0002). PTEN extent of expression was significantly lower in pts with PCa recurrence compared to controls (p=0.02). The control group demonstrated a significantly higher intensity (2+ or 3+) of PTEN staining (p=0.05). Lack of PTEN expression, as well as low PTEN expression (extent <10%), was more frequently encountered in recurrent PCa (p<0.0001). However, the protective effect of PTEN expression was non-linear based on H-score levels. Concurrent TMPRSS2-ERG fusion had no additive effect to loss of PTEN in predicting PCa recurrence. Although tumors with concurrent Chromososme 21 polyploidy and PTEN loss were more likely to recur (OR:4.7) compared to those with PTEN loss alone (OR:3.2), the interaction between the two parameters was not synergistic in effect. CONCLUSIONS Lack of PTEN expression in PCa predicted higher likelihood of disease recurrence in our matched case-control cohort. A PTEN immunoexpression extent higher than 10% seems to exert a positive, albeit non-linear, effect on PCa outcome. We found no evidence of synergistic interaction between PTEN loss and presence of TMPRSS2-ERG fusion or between PTEN loss and Chromosome 21 polyploidy in predicting PCa recurrence. Baltimore, MD© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e827 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Luciana Schultz More articles by this author Elizabeth Platz More articles by this author Antoun Toubaji More articles by this author Roula Albadine More articles by this author Jessica Hicks More articles by this author William Isaacs More articles by this author Christian McEvoy More articles by this author Alan Meeker More articles by this author Angelo De Marzo More articles by this author George Netto More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

CK2β Is Expressed in Endometrial Carcinoma and Has a Role in Apoptosis Resistance and Cell Proliferation

Protein kinase CK2 (CK2) is a serine/threonine kinase that participates in important cellular processes. We have recently demonstrated that CK2 plays a role in resistance to TRAIL/Fas-induced apoptosis in endometrial carcinoma (EC) by regulating FLIP. Here, we assessed the immunohistochemical expression of CK2beta in EC and checked its role in cell proliferation and anchorage-independent cell growth. CK2beta immunostaining was assessed in two tissue microarrays, one constructed from paraffin-embedded blocks of 95 ECs and another from 70 samples of normal endometrium. CK2beta expression was correlated with histological type; grade and stage; cell proliferation (Ki-67) and apoptotic index; immunostaining for cyclin D1, PTEN, AKT, beta-catenin, and FLIP. Moreover, the Ishikawa EC cell line was subjected to down-regulation of CK2 by shRNA. CK2beta expression was frequent in EC (nuclear, 100%; cytoplasmic, 87.5%). The staining was more intense in EC than in normal endometrium (P = 0.000), and statistically correlated with AKT, PTEN, beta-catenin, and FLIP. In EC, CK2beta expression correlated with cell proliferation. Knock-down of CK2beta blocked colony formation of EC in soft agar, and also resulted in decreased expression of cyclin D1 and ERK phosphorylation. The results confirm that CK2beta is widely expressed in EC, and suggest a role in cell proliferation and anchorage-independent cell growth.

L’expression immunohistochimique de l’antigène PTEN : Un nouvel outil diagnostique dans les néoplasies débutantes de l’endomètre

We examined immunohistochemical PTEN protein expression in endometrial samples obtained from perimenopausal women with uterine bleeding in order to diagnose early endometrial neoplasia. Paraffin sections of endometrial samples (biopsies, endometrium resection, hysterectomy) were reviewed and tested for immunocytochemical PTEN expression by epithelial cells. Immunohistochemical studies were performed with the Ventana Benchmark device and the immunoperoxidase technique with monoclonal anti-PTEN (6H2.1/Cascade Biosciences). We studied 45 samples of proliferative endometria, 42 samples of atypical hyperplasia (neoplasia), and 55 samples of endometrial carcinomas (30 endometrioid, 5 serous papillary, 10 clear cell, 5 adenosquamous, and 5 MMMT). A strong positive PTEN immunoreaction was observed in all 45 normal proliferative endometria, 2/30 endometrioid carcinomas, and 23/25 non endometrioid carcinomas. In contrast, PTEN immunoexpression was negative or weak in 40/42 atypical hyperplasia and 28/30 endometrioid carcinomas. Negative or weak PTEN expression correlated with endometrial neoplasia (atypical proliferation) (p < 0.001). Thus (i) PTEN immunoexpression in endometrial paraffin sections is a new diagnostic tool, distinguishing PTEN-positive cyclic abnormal monoclonal proliferative endometrium (anovulatory, non atypical, simple and complex hyperplasia) from PTEN-negative (or decreased) endometrial neoplasia, and especially early endometrial neoplasia (atypical simple and complex hyperplasia, in situ carcinoma, superficial carcinoma with focal invasion). (ii) Given the lack of reproducibility of histological identification of atypical (precancerous invasive) and non atypical (precancerous non invasive) endometrial hyperplasia, the new criteria (PTEN-negative crowded glands, gland/stroma ratio > 55%, nuclear pleomorphism, in areas > 1 mm) recently proposed to diagnose early endometrial neoplasia appear to be clinically relevant.