Association of nuclear accumulation of p53 with ERG fusion and poor prognosis in prostate cancer.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 124-124
Author(s):  
Sarah Minner ◽  
Antje Krohn ◽  
Hueseyin Sirma ◽  
Ronald Simon ◽  
Markus Graefen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Poor Prognosis ◽  
Statistical Power ◽  
Tumor Stage ◽  
Nuclear Accumulation ◽  
Cancer Tissue ◽  
Positive Staining ◽  
Advanced Tumor Stage ◽  
Advanced Tumor ◽  
Psa Recurrence

124 Background: We have previously shown that nuclear accumulation of p53 is rare in prostate cancer but strongly linked to early biochemical recurrence (Schlomm et al., Modern Pathology, 2008). The current study was designed to study the association between ERG fusion and p53 in a large series of prostate cancers. Methods: A prostate cancer tissue microarray (TMA) was constructed from 4,699 radical prostatectomie specimens with histological, pathological, and clinical follow-up data. Immunohistochemistry was applied to detect nuclear p53 accumulation as a marker for defective p53 and to detect ERG expression as a surrogate for ERG gene fusion. Results: Nuclear accumulation of p53 was detected in 62/3,667 (1.7%) analyzable tissue spots. Positive staining was significantly linked to advanced tumor stage (p<0.0001), high Gleason score (p<0.0001), presence of lymph node metastases (p=0.0005), and early PSA recurrence (p<0.0001) in all cancers. ERG expression was found in 1,990/4,266 (46.6%) analyzable cancers, but was unrelated to tumor phenotype or patient prognosis. Results of both p53 and ERG were available from 3,392 tumors. Presence of nuclear p53 staining was linked to ERG fusion positive cancers: 40 (2.7%) of 1,491 ERG-positive cancers, but only 20 (1.1%) of 1,901 ERG-negative tumors showed nuclear p53 staining (p=0.0004). A Kaplan-Meier survival analysis of p53 in the subsets of 1,699 ERG positive and 1,280 ERG negative cancers revealed that nuclear p53 accumulation was strongly linked to early PSA recurrence in both subsets (p<0.0001 each). Conclusions: These data demonstrate that the poor prognosis of prostate cancer patients with nuclear p53 accumulation is independently from the ERG fusion status, but suggest a distinct biological role of p53 inactivation in ERG fusion positive cancers. The very high number of prostate cancer samples included in the TMA used in this study allows for analysis of rare events such as p53 alterations with high statistical power.

Chromosomal deletions, tumor phenotype, and prognosis in prostate cancer.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 37-37
Author(s):  
S. Minner ◽  
A. Krohn ◽  
L. Burkhardt ◽  
P. Tennstedt ◽  
R. Simon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Array Cgh ◽  
Tumor Stage ◽  
Fish Analysis ◽  
Gleason Grade ◽  
Advanced Tumor Stage ◽  
Chromosomal Deletions ◽  
Advanced Tumor ◽  
Psa Recurrence ◽  
Tumor Phenotype

37 Background: Chromosomal deletions are frequent in prostate cancer (PCa) but target genes and potential clinical significance are often unknown. This project aimed at the identification of frequent and new deletions in PCa and to study their association with tumor phenotype and PSA recurrence. Methods: Array CGH was performed on 77 advanced PCa. Deletions of interest were subsequently analyzed on a tissue microarray containing more than 2000 PCa with clinical follow-up data using fluorescence in situ hybridization (FISH). The FISH probes used included a break-apart probe for TMPRSS2-ERG and dual-labeling probes for centromere 10/PTEN and centromere 3/3p14. Results: The most frequent circumscribed deletions found by array CGH were 3p14 (including FOXP1) in 18%, 5q31 in 16%, 5q21 in 14%, 6q13 in 21%, 6q21 in 19%, 6q26 in 14%, 8p11 in 17%, 10q23 (including PTEN) in 18%, 12p13 in 14%, 13q14 in 14%, 16q24 in 22% and 21q (representing TMPRSS2-ERG fusion) in 18%. TMPRSS2-ERG fusions, PTEN and FOXP1 deletions were selected for FISH analysis. A TMPRSS2-ERG fusion was observed in 394 of 947 interpretable cases (41.6%). TMPRSS2-ERG fusion was unrelated to tumor stage, Gleason grade, and PSA recurrence. PTEN deletions were observed in 8.9% of 1844 interpretable cases and were associated with advanced tumor stage (p<0.0001), high Gleason grade (p<0.0001), and early biochemical recurrence (p<0.0001). FOXP1 deletions were seen in 5.0% of 619 cases. FOXP1 deletions were not significantly linked to tumor phenotype and outcome. Both PTEN and FOXP1 deletions were strongly linked to TMPRSS2-ERG fusions. TMPRSS2-ERG fusion positive tumors had PTEN deletions in 15.4% and FOXP1 deletions in 10.7%, while TMPRSS2-ERG fusion negative cancers had PTEN deletions in only 5.8% and FOXP1 deletions in only 2.0% of cases (p<0.0001 each). Conclusions: The TMPRSS2-ERG fusion determines a genetically distinct subgroup of prostate cancers. Our data provide no evidence for a particular clinical behaviour of TMPRSS2-ERG fusion positive cancers in radically operated patients. PTEN and FOXP1 alterations are preferentially found in TMPRSS2-ERG fusion positive cancers. Both genes may potentially be involved in pathway dysregulation in these cancers. No significant financial relationships to disclose.

scholarly journals E-Cadherin expression in human tumors: a tissue microarray study on 10,851 tumors

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Eike Burandt ◽  
Felix Lübbersmeyer ◽  
Natalia Gorbokon ◽  
Franziska Büscheck ◽  
Andreas M. Luebke ◽  
...  
Keyword(s):  
Tissue Microarray ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Lobular Carcinoma ◽  
Tumor Stage ◽  
Advanced Tumor Stage ◽  
Carcinoma Of The Breast ◽  
Advanced Tumor ◽  
Tumor Entities ◽  
E Cadherin

Abstract Background The E-Cadherin gene (CDH1, Cadherin 1), located at 16q22.1 encodes for a calcium-dependent membranous glycoprotein with an important role in cellular adhesion and polarity maintenance. Methods To systematically determine E-Cadherin protein expression in normal and cancerous tissues, 14,637 tumor samples from 112 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format. Results E-Cadherin was strongly expressed in normal epithelial cells of most organs. From 77 tumor entities derived from cell types normally positive for E-Cadherin, 35 (45.5%) retained at least a weak E-Cadherin immunostaining in ≥99% of cases and 61 (79.2%) in ≥90% of cases. Tumors with the highest rates of E-Cadherin loss included Merkel cell carcinoma, anaplastic thyroid carcinoma, lobular carcinoma of the breast, and sarcomatoid and small cell neuroendocrine carcinomas of the urinary bladder. Reduced E-Cadherin expression was linked to higher grade (p = 0.0009), triple negative receptor status (p = 0.0336), and poor prognosis (p = 0.0466) in invasive breast carcinoma of no special type, triple negative receptor status in lobular carcinoma of the breast (p = 0.0454), advanced pT stage (p = 0.0047) and lymph node metastasis in colorectal cancer (p < 0.0001), and was more common in recurrent than in primary prostate cancer (p < 0.0001). Of 29 tumor entities derived from E-Cadherin negative normal tissues, a weak to strong E-Cadherin staining could be detected in at least 10% of cases in 15 different tumor entities (51.7%). Tumors with the highest frequency of E-Cadherin upregulation included various subtypes of testicular germ cell tumors and renal cell carcinomas (RCC). E-Cadherin upregulation was more commonly seen in malignant than in benign soft tissue tumors (p = 0.0104) and was associated with advanced tumor stage (p = 0.0276) and higher grade (p = 0.0035) in clear cell RCC, and linked to advanced tumor stage (p = 0.0424) and poor prognosis in papillary RCC (p ≤ 0.05). Conclusion E-Cadherin is consistently expressed in various epithelial cancers. Down-regulation or loss of E-Cadherin expression in cancers arising from E-Cadherin positive tissues as well as E-Cadherin neo-expression in cancers arising from E-Cadherin negative tissues is linked to cancer progression and may reflect tumor dedifferentiation.

scholarly journals HSD17B6 downregulation predicts poor prognosis and drives tumor progression via activating Akt signaling pathway in lung adenocarcinoma

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Tian Tian ◽  
Fu Hong ◽  
Zhiwen Wang ◽  
Jiaru Hu ◽  
Ni Chen ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Lung Adenocarcinoma ◽  
Poor Prognosis ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Grade ◽  
Tumor Stage ◽  
Advanced Tumor Stage ◽  
Large Tumor ◽  
Mesenchymal Transition ◽  
Advanced Tumor

AbstractLung adenocarcinoma is one of the most frequent tumor subtypes, involving changes in a variety of oncogenes and tumor suppressor genes. Hydroxysteroid 17-Beta Dehydrogenase 6 (HSD17B6) could synthetize dihydrotestosterone, abnormal levels of which are associated with progression of multiple tumors. Previously, we showed that HSD17B6 inhibits malignant progression of hepatocellular carcinoma. However, the mechanisms underlying inhibiting tumor development by HSD17B6 are not clear. Moreover, its role in lung adenocarcinoma (LUAD) is yet unknown. Here, we investigated its expression profile and biological functions in LUAD. Analysis of data from the LUAD datasets of TCGA, CPTAC, Oncomine, and GEO revealed that HSD17B6 mRNA and protein expression was frequently lower in LUAD than in non-neoplastic lung tissues, and its low expression correlated significantly with advanced tumor stage, large tumor size, poor tumor differentiation, high tumor grade, smoking, and poor prognosis in LUAD. In addition, its expression was negatively regulated by miR-31-5p in LUAD. HSD17B6 suppressed LUAD cell proliferation, migration, invasion, epithelial–mesenchymal transition (EMT), and radioresistance. Furthermore, HSD17B6 overexpression in LUAD cell lines enhanced PTEN expression and inhibited AKT phosphorylation, inactivating downstream oncogenes like GSK3β, β-catenin, and Cyclin-D independent of dihydrotestosterone, revealing an underlying antitumor mechanism of HSD17B6 in LUAD. Our findings indicate that HSD17B6 may function as a tumor suppressor in LUAD and could be a promising prognostic indicator for LUAD patients, especially for those receiving radiotherapy.

ΔTAp73 Upregulation Correlates With Poor Prognosis in Human Tumors: Putative In Vivo Network Involving p73 Isoforms, p53, and E2F-1

2006 ◽  
Vol 24 (5) ◽  
pp. 805-815 ◽  
Author(s):  
Gemma Domínguez ◽  
José M. García ◽  
Cristina Peña ◽  
Javier Silva ◽  
Vanesa García ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Cell Transformation ◽  
Tumor Stage ◽  
Advanced Tumor Stage ◽  
Breast Cancer Patients ◽  
Oncogenic Ras ◽  
Advanced Tumor ◽  
Tumor Tissues ◽  
Ras Status

Purpose Although full-length TAp73 variants largely mimic p53 suppressor activities, the transactivation-deficient transcripts ΔTAp73 exert an oncogenic effect by inactivating p53 and TAp73 suppressor properties. Additionally, ΔTAp73 may cooperate with oncogenic RAS to induce cell transformation, confer drug resistance, and induce the phosphorylation of phosphorylated Rb. Here, we study the expression of TAp73 and ΔTAp73 variants and assess possible associations with E2F-1, p53 and K-ras status. We address the possible clinical relevance of alterations in these genes. Patients and Methods We determine in 113 colon and 60 breast cancer patients (a) the expression levels of TAp73, ΔTAp73 (ΔEx2p73, ΔEx2/3p73, and ΔNp73), and E2F-1 transcripts by quantitative real-time reverse transcriptase polymerase chain reaction (PCR); (b) mutations in the first exon of K-ras by PCR–single-stranded confirmational polymorphism; and (c) p53 status by immunohistochemistry. Tumor characteristics were examined in each patient. Results Both suppressor and oncogenic isoforms of TP73 were significantly coupregulated in tumor tissues. Associations were observed between (a) p53 wild type status and upregulation of some TP73 variants; (b) overexpression of E2F-1 and some TP73 forms; and (c) upregulation of ΔTAp73 variants and advanced pathologic stage, lymph node metastasis, vascular invasion, presence of polyps, and tumor localization. Conclusion Overexpression of TP73 variants in tumor tissues indicates that they may be involved in colon and breast carcinogenesis. The association between upregulation of ΔTAp73 isoforms and poor prognosis features, specifically advanced tumor stage, suggests that they may be of practical clinical prognostic value. Interestingly, the in vivo associations identified here may indicate a functional network involving p73 variants, p53, and E2F-1.

scholarly journals MAGEA3 Expression in Cutaneous Squamous Cell Carcinoma Is Associated with Advanced Tumor Stage and Poor Prognosis

2017 ◽  
Vol 137 (3) ◽  
pp. 775-778 ◽  
Author(s):  
Melody Abikhair ◽  
Nazanin Roudiani ◽  
Hiroshi Mitsui ◽  
James G. Krueger ◽  
Anna Pavlick ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Poor Prognosis ◽  
Tumor Stage ◽  
Cutaneous Squamous Cell Carcinoma ◽  
Advanced Tumor Stage ◽  
Advanced Tumor

scholarly journals Epithelial splicing regulatory protein 1 and 2 (ESRP1 and ESRP2) upregulation predicts poor prognosis in prostate cancer

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Morton Freytag ◽  
Martina Kluth ◽  
Elena Bady ◽  
Claudia Hube-Magg ◽  
Georgia Makrypidi-Fraune ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Regulatory Protein ◽  
Tumor Stage ◽  
Molecular Data ◽  
Prognostic Impact ◽  
Advanced Tumor Stage ◽  
Nuclear Staining ◽  
Prognostic Features ◽  
Advanced Tumor ◽  
The Impact

Abstract Background Epithelial splicing regulatory protein 1 (ESRP1) and 2 (ESRP2) regulate alternative splicing events of various pre-mRNAs. Some of these targets play a role in cancer-associated processes, including cytoskeleton reorganization and DNA-repair processes. This study was undertaken to estimate the impact of ESRP1 and ESRP2 alterations on prostate cancer patient prognosis. Methods A tissue microarray made from 17,747 individual cancer samples with comprehensive, pathological, clinical and molecular data was analyzed by immunohistochemistry for ESRP1 and ESRP2. Results Nuclear staining for ESRP1 was seen in 38.6% (36.0% low, 2.6% high) of 12,140 interpretable cancers and in 41.9% (36.4% low, 5.3% high) of 12,962 interpretable cancers for ESRP2. Nuclear protein expression was linked to advanced tumor stage, high Gleason score, presence of lymph node metastasis, early biochemical recurrence, and ERG-positive cancers (p < 0.0001 each). Expression of ESRPs was significantly linked to 11 (ESRP1)/9 (ESRP2) of 11 analyzed deletions in all cancers and to 8 (ESRP1)/9 (ESRP2) of 11 deletions in ERG-negative cancers portending a link to genomic instability. Combined ESRPs expression analysis suggested an additive effect and showed the worst prognosis for cancers with high ESRP1 and ESRP2 expression. Multivariate analyses revealed that the prognostic impact of ESRP1, ESRP2 and combined ESRP1/ESRP2 expression was independent of all established pre- and postoperative prognostic features. Conclusions Our data show a striking link between nuclear ESRP expression and adverse features in prostate cancer and identifies expression of ESRP1 and/or ESRP2 as independent prognostic markers with a potential for routine application.

scholarly journals The Association between Plasma Levels of Intact and Cleaved uPAR Levels and the Risk of Biochemical Recurrence after Radical Prostatectomy for Prostate Cancer

Diagnostics ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 877
Author(s):  
Hein Vincent Stroomberg ◽  
Gitte Kristensen ◽  
Kasper Drimer Berg ◽  
Solvej Lippert ◽  
Klaus Brasso ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radical Prostatectomy ◽  
Plasma Levels ◽  
Biochemical Recurrence ◽  
Specific Antigen ◽  
Predictive Biomarkers ◽  
Tumor Stage ◽  
Advanced Tumor Stage ◽  
Urokinase Plasminogen Activator Receptor ◽  
Advanced Tumor

Radical prostatectomy (RP) is a curatively intended treatment option for clinically localized non-metastatic prostate cancer (PCa). Novel biomarkers could refine treatment choice based on a better identification of men at risk of biochemical recurrence (BCR) following therapy. The urokinase plasminogen activator receptor (uPAR) system is a promising biomarker of aggressiveness in many cancers. The predictive value of uPAR after curatively intended treatment for PCa remains to be elucidated. This was a prospective evaluation of uPAR analysis in men with prostate cancer (Copenhagen uPAR prostate cancer (CuPCA) database). Risk of BCR following RP was analyzed using cumulative incidences with competing risk and tested with Gray’s test. Associations between quartile groups of uPAR levels and BCR were assessed with uni- and multivariate Cox proportional hazards. In total, 532 men were included. With more advanced tumor stage, Gleason score (GS), and prostate-specific antigen (PSA) the uPAR I–III + II–III plasma levels increased. Quartile levels of plasma uPAR I–III, I–III + II–III showed no significant association between the risk of BCR and the plasma uPAR levels in uni- and multivariate analysis. Despite increased levels of uPAR I–III + II–III in advanced tumor stage, intact and cleaved uPAR levels were not associated with BCR and are not predictive biomarkers for BCR following curatively intended treatment of PCa. It is unlikely that further studies of uPAR in RP treated patients is needed.

Hypermethylation of MCAM gene is associated with advanced tumor stage in prostate cancer

The Prostate ◽  
2008 ◽  
Vol 68 (4) ◽  
pp. 418-426 ◽  
Author(s):  
Jun-Wei Liu ◽  
Jatin K. Nagpal ◽  
Carmen Jeronimo ◽  
Ji Eun Lee ◽  
Rui Henrique ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Stage ◽  
Advanced Tumor Stage ◽  
Advanced Tumor
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