scholarly journals Heterogeneity of Ki-67 and p53 Expression in Glioblastoma

2014 ◽  
Vol 14 (1) ◽  
pp. 11-14 ◽  
Author(s):  
Arvids Jakovlevs ◽  
Andrejs Vanags ◽  
Dainis Balodis ◽  
Janis Gardovskis ◽  
Ilze Strumfa
Keyword(s):  
Protein Expression ◽  
Diagnostic Accuracy ◽  
Cellular Proliferation ◽  
P53 Protein ◽  
World Health ◽  
Residual Tumour ◽  
Ki 67 ◽  
P53 Expression ◽  
Proliferation Activity ◽  
The Mean

Summary Introduction. Heterogeneity is a characteristic feature of malignant tumours. It challenges the treatment regimens as well as can impair the diagnostic accuracy. Glioblastoma multiforme (GBM), a high-grade malignant glial tumour, is known for the extreme morphological heterogeneity giving rise also to the term itself. Aim of the study was to evaluate heterogeneity of pathogenetically and diagnostically important cardinal tumour features, namely, cellular proliferation and tumour suppressor protein expression in GBMs. Material and methods. The study group comprised 101 GBMs, retrospectively identified by archive search. The inclusion criteria comprised validated diagnosis (by World Health Organisation criteria) and lack of prior treatment. Recurrent GBMs as well as other glial and non-glial tumours were excluded from the study. Insufficient tissue materials comprising stereotactic biopsies and tissues affected by widespread necrosis (exceeding 90%) were also excluded. Proliferation activity (by Ki-67) and expression of aberrant p53 protein was detected by immunohistochemical investigation (IHC) of formalin-fixed, paraplast-embedded tumour samples. Polymeric visualisation system was used to detect bound primary antibodies. The expression of each antigen was measured by computed morphometry in at least 200 cells of hot and cold spots in each tumour. The data were expressed as the relative value. Heterogeneity was estimated as the mathematical difference between the highest and lowest expression value in each tumour. Descriptive statistics was applied. The 95% confidence intervals (CI) were determined as well. Results. The highest proliferation activity ranged 15 – 95%; mean 43.9% [95% CI = 40.3 – 47.6]. The lowest proliferation activity ranged 2 – 95%, mean 20.1% [16.8 – 23.4]. The mean proliferation heterogeneity was 23.8% [21.5 – 26.2]; range 0 – 67%. The mean heterogeneity of p53 protein expression was 11.7% [8.9 – 14.6], ranging 0 – 75%. Conclusions. GBM is characterized by marked heterogeneity regarding proliferation rate and expression of p53 protein that may affect diagnostic accuracy and grading of gliomas in small samples of tissue material as well as survival in case of small residual tumour after surgical treatment.

Immunohistochemical study of p53 expression in endometrial carcinomas: correlation with markers of proliferating cells and clinicopathologic features

1993 ◽  
Vol 3 (6) ◽  
pp. 363-368 ◽  
Author(s):  
T. Hachisuga ◽  
K. Fukuda ◽  
M. Uchiyama ◽  
N. Matsuo ◽  
T. Iwasaka ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Proliferative Activity ◽  
P53 Protein ◽  
Myometrial Invasion ◽  
Proliferating Cells ◽  
Ki 67 ◽  
Normal Endometrium ◽  
P53 Expression ◽  
Dna Polymerase Α ◽  
Endometrial Carcinomas

Using anti-p53 (PAb1801 and PAb240), anti-DNA polymerase α and Ki-67 monoclonal antibodies, the expression of p53 was studied in 11 normal endometria, 14 endometrial hyperplasias and 27 endometrial carcinomas and its relationship to the proliferative activity of the tumors was examined. Normal endometria and simple hyperplasias were completely negative for p53. The PAb1801 indices of complex hyperplasias and complex atypical hyperplasias were 2.5±1.8% and 5.0±3.2%, respectively. The PAb1801 indices of grade 1, grade 2 and grade 3 endometrial carcinomas were 10.2±14.2%, 44.4±29/0% and 45.0±32.5%, respectively. These results indicate a progressively enhanced p53 expression in the sequence from normal endometrium, through hyperplasia to carcinoma. A significant correlation between p53 expression and labeling indices of Ki-67 and DNA polymerase α was observed in endometrial carcinomas. The endo-metrial carcinomas with p53 overexpression developed mainly in post-menopausal patients and were frequently high-grade tumors with deep myometrial invasion. These findings may indicate that overexpression of p53 protein contributes to the proliferative activity of the tumor cells.

P53 expression as a predictor of recurrence in cervical squamous cell carcinoma

2002 ◽  
Vol 12 (3) ◽  
pp. 299-303 ◽  
Author(s):  
S. M. F Brenna ◽  
L. C Zeferino ◽  
G. A Pinto ◽  
R. A Souza ◽  
L. A. L Andrade ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Protein Expression ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
P53 Protein ◽  
Figo Stage ◽  
Cervical Squamous Cell Carcinoma ◽  
Stage Ii ◽  
P53 Expression ◽  
P53 Protein Expression

Abstract.Brenna SMF, Zeferino LC, Pinto GA, Souza RA, Andrade LAL, Vassalo J, Martinez EZ, Syrjänen KJ. P53 expression as a predictor of recurrence in cervical squamous cell carcinoma.P53 protein function is frequently down-regulated in cervical cancer by complexing with human papillomavirus (HPV) E6 protein, leading to degradation of p53, genomic instability, and mutations. Results are controversial, however, on the prognostic value of p53 protein expression in cervical cancer. In this study, a cohort of 220 Brazilian women with FIGO stage IB-III cervical squamous cell carcinoma (SCC), followed for 5 years, was analyzed for p53 protein expression using immunohistochemistry. The disease-free survival (DFS) and relapse rate were analyzed using univariate (Kaplan-Meier) and multivariable (Cox's proportional hazards model) survival analyses. P53 protein expression was detected in 35% of the patients, including 21% in stage I, 28% in stage II and 51% in stage III of disease. Of 220 women, only 116 completed one of the treatment options standardized by FIGO within 120 days. There was a higher risk of relapse in stage II and III disease, that was not modified by p53 positivity; HR 3.0 (1.3–6.5) to stage II and HR 4.0 (1.9–8.5) to stage III. The multivariate analysis evidenced that p53 expression is not an independent factor exceeding the power of FIGO stage as the single most important determinant of the hazards for disease relapse.

Igf-Ii Mrna Expression in Breast Cancer: Predictive Value and Relationship to Other Prognostic Factors

2010 ◽  
Vol 25 (3) ◽  
pp. 150-156 ◽  
Author(s):  
Emilio Fiore ◽  
Daniela Campani ◽  
Ilaria Muller ◽  
Valentina Belardi ◽  
Elisa Giustarini ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prognostic Factors ◽  
Mrna Expression ◽  
Ductal Carcinoma ◽  
P53 Protein ◽  
Independent Predictive Factor ◽  
Ki 67 ◽  
P53 Expression ◽  
Predictive Parameters ◽  
The Difference

Purpose Insulin-like growth factor-II (IGF-II) is an important regulator of tumor growth in breast cancer. In this study we have examined the prognostic value of IGF-II mRNA expression in breast cancer and its relationship to other predictive parameters. Patients Sixty-eight women with infiltrating ductal carcinoma were given the same treatments including mastectomy and antitumoral therapies and followed up for 5 years. Results The overall 5-year survival rate was 73.5% (55/68). IGF-II mRNA was expressed in 33/64 patients (51.6%) and had no significant impact on survival. The expression of estrogen receptor (ER) and progesterone receptor (PgR) did not significantly affect the 5-year survival, but in the presence of an IGF-II mRNA signal, the survival of ER- and PgR-negative patients (n=9) was lower than that of ER- and PgR-positive patients (n=15), although the difference was not significant. The 5-year survival was not significantly different between Ki-67-positive and negative patients, but in the IGF-II positive group Ki-67-positive patients (n=7) had a significantly poorer prognosis than Ki-67-negative patients (n=26). The expression of p53 protein was associated with a poorer prognosis: 6/11 (54.5%) p53-positive patients died in the first 26 months of follow-up and 5 of these 6 patients (83.3%) also had positive IGF-II mRNA expression. Conclusions IGF-II mRNA expression per se is not an independent predictive factor in breast cancer but may be a marker of poor prognosis when associated with other prognostic factors such as Ki-67 index and p53 expression.

P53 Protein Expression Levels Are Prognostic in AML and Predict for Mutational Status.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2397-2397 ◽  
Author(s):  
Steven M. Kornblau ◽  
Joseph Barnett ◽  
YiHua Qiu ◽  
Wenjing Chen ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Protein Expression ◽  
P53 Protein ◽  
Leukemia Cell ◽  
Response To Therapy ◽  
Newly Diagnosed ◽  
P53 Expression ◽  
Mutation Status ◽  
Expression Levels ◽  
P53 Protein Expression ◽  
Very High

Abstract Mutation of the P53 gene in AML confers an adverse prognosis and is associated with unfavorable cytogenetics typically with complex karyoptyes. Since P53 function can also be modulated by MDM2 associated, ubiquitin dependent, destruction, the amount of P53 protein may also be relevant to leukemia blast biology. Previous studies have focused on the presence or absence of mutations, but have not examined the relevance of protein expression levels. We evaluated the levels of expression of P53 using high-throughput reverse phase protein array technology (RPPA) on 537 leukemia cell enriched samples from 423 patients (258 newly diagnosed, 47 primary refractory, 118 relapse 1, 2 or refractory). Levels of P53 were lower, equal and higher than that of normal CD34+ cells in 57%, 37% and 16% of cases, respectively. Almost all cases with very high P53 had unfavorable cytogenetics with complex karyotypes (15/16 newly diagnosed), and very high P53 was observed in 13% of patients with unfavorable cytogenetics compared to <1% with favorable or intermediate cytogenetics. Changes involving chromosome 5 (66% vs. 9%) and 7 (50% vs. 11%) were very common in those with very high P53 compared to those with normal or low P53. Levels of expression were similar regardless of disease status; newly diagnosed, primary refractory or relapsed We tested the hypothesis that patients with very high P53 were likely to have mutations by performing RT-PCR sequencing, covering exons 5–9 in 23 very high, and 11 low P53 expressing patients. Among very high expressers 11 missense mutations were found in 9 patients (39% overall), including 7 of 13 newly diagnosed cases (54%) compared to 0 of 11 low expressers (p=0.02 all cases, 0.05 newly diagnosed). Mutations occurred at known hot spots: including 5 in exon 8 [3 at codon 273], 3 in exon 7 and 2 in exon 5 and 6. High P53 expression was inversely correlated with PTEN expression (P=0.001, see accompanying abstract). Expression was unaffected by FLT3-ITD mutation status. For outcome analysis, martingale residuals were utilized to define an optimal cutpoint for dichotomization into groups with Higher (n=57, 50 treated) vs. lower (n=201, 165 treated) P53. Patients with higher P53 were significantly more likely to have an antecedent hematological disorder (37% vs. 17%, P=0.002) and unfavorable cytogenetics (65% vs. 39%, P=0.0002). Response to therapy and outcome were significantly worse in those with higher P53. The complete remission rate was significantly lower in those with higher P53 (46% vs. 66%, P=0.01). The relapse rate was significantly higher (74% vs. 47%, P=0.02) and the median remission duration was significantly shorter (26 vs. 43 weeks, P=0.02). The combination resulted in a significantly shorter median survival (26 vs. 44 weeks, P=0.0003). Analysis of MDM2 expression in these same cases is underway. This data demonstrates that cases of AML with very high levels of P53 protein expression, measured by RPPA, are frequently found in those with P53 mutations. Not all patients with high P53 levels have mutations, but high levels of P53 protein carry an adverse prognosis, regardless of mutation status.

High P53 Protein Expression Level Independent of Mutational Status Is An Adverse Prognostic Factor for Survival in Acute Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1490-1490 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Yi Hua Qiu ◽  
Sean Post ◽  
Steven M. Kornblau
Keyword(s):  
Overall Survival ◽  
Protein Expression ◽  
Myeloid Leukemia ◽  
P53 Protein ◽  
P53 Mutations ◽  
P53 Expression ◽  
The Poor ◽  
P53 Protein Expression ◽  
Mutational Status ◽  
Acute Myeloid

Abstract Abstract 1490 Background: The tumor suppressor p53 is frequently mutated in human cancer, including acute myeloid leukemia (AML). In AML, p53 mutations have been associated with poor risk cytogenetics (i.e. complex karyotype, −5/−7). However, the function of p53 can also be compromised by protein stabilization and/or expression. The implications of p53 protein expression have not been studied in AML. Methodology: We assessed p53 expression by high-throughput reverse phase protein array (RPPA) technology in 511 pts (719 samples). Eleven CD34+ bone marrow (BM) and 10 normal peripheral blood (PB) lymphocyte samples were used as controls. Samples were printed as 5 serial 1: 2 dilutions in duplicate using an Aushon 2470 Arrayer. Mutational status was determined by Sanger sequencing of exons 5 through 9 of the p53 gene. Results: Paired PB- and BM-derived AML samples expressed similar p53 levels (p=0.25). A trend towards higher p53 expression at relapsed was observed among 47 paired diagnosis/relapse samples (p=0.07). Cases of AML-M3 and –M6 exhibited higher expression of p53 than other FAB subtypes. p53 expression directly correlated with age (p=0.01) and CD34 (p=0.001) and inversely correlated with WBC (p=0.007), BM (p=0.0001) and PB (p=0.0001) blasts, platelets (p=0.007), HLA-DR (p=0.01), CD19 (p=0.02), and survival (p=0.01). High p53 (p53high) expression level was more associated with unfavorable cytogenetics than with favorable or intermediate cytogenetics (p=0.00001). When all cytogenetic abnormalities were considered, pts with −5 had the highest levels of p53 (p=0.00001). Pts with RAS mutations, but not those with FLT3-ITD, NPM1, or IDH1/2, had lower levels of p53 protein. When pts were divided according to the level of p53 protein expression p53high was associated with lower complete remission (CR) rates (51% vs 56%; p=??) and higher relapsed rates (82% vs 62%; p=??). The median overall survival (OS) of pts with p53high and p53low were 29.8 vs. 51 wks (p=0.009). Most cases with p53high had unfavorable cytogenetics and the effect on OS was predominantly seen in that subpopulation with p53high and p53low pts living a medina of 23.4 vs. 36 wks (p=0.07), respectively. In order to determine whether the poor outcomes associated with p53high were due to the presence of a higher rate of p53 mutations among pts with p53high, we determined the p53 mutational status of 55 pts. p53high was highly correlated with the presence of p53 mutations as the latter were detected in 17/40 pts with p53high but in only 1/16 pts with p53low. Importantly, the presence of p53high, both in the presence (29 wks) or in the absence (24 wks) of p53 mutations, was associated with significantly worse overall survival compared with pts with p53low (56 wks; p=0.05, Figure 1). Multivariate analysis indicated that p53 is a significant independent risk factor for survival in AML. The final model included: age (p=0.000001), favorable cytogenetics (0.01), unfavorable cytogenetics (p=0.00001), WBC (p=0.0005), albumin (p=0.0003), FLT3-ITD (P=0.04), and P53 (P=0.02). p53high was positively correlated with p53pSER15 (p=0.00001), Rbp807p811 (p=0.0002), c-MET (p=0.01), FoxO3a (p=0.004), KIT (p=0.001), p38p180p182 (p0.02), BAD (p=0.0001), cleaved PARP (p=0.002), cleaved PARP (p=0.01), TCF4 (p=0.02), fibronectin (p=0.02), and hsp70 (p=0.003), and negatively with AKTp473 (p=0.01), ERK (p=0.002), mTOR (p=0.005), PI3Kp85 (p=0.002), PKCδ (p=0.00002), GAB2 (p=0.00005), beclin (p=0.007), JMJD6 (p=0.001), Gata3 (p=0.02), p21 (p=0.01), and Mdm2 (p=0.001). Conclusions: Our results suggest that high levels of p53 protein constitute a powerful marker of short survival in AML. This effect is independent of p53 mutational status. The poor outcome of pts with high level of expression of p53 in the absence of p53 mutations suggests that the p53 pathway may be functionally perturbed in a much higher proportion of pts with AML than previously recognized. These data support the use of p53 protein expression levels in prognostication and in the development of targeted therapeutics. Disclosures: No relevant conflicts of interest to declare.

p53 Expression in B-Cell Chronic Lymphocytic Leukemia: A Marker of Disease Progression and Poor Prognosis

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4342-4349 ◽  
Author(s):  
Iole Cordone ◽  
Serena Masi ◽  
Francesca Romana Mauro ◽  
Silvia Soddu ◽  
Ornella Morsilli ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Protein Expression ◽  
P53 Protein ◽  
Clinical Stage ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
P53 Expression ◽  
Short Survival ◽  
P53 Protein Expression ◽  
Cell Chronic Lymphocytic Leukemia

We have analyzed by immunocytochemistry (ICC) the frequency of p53 protein expression in 181 cases of B-cell chronic lymphocytic leukemia (CLL) followed at a single institution to assess the relationship between p53 and the clinical and morphological features of the disease, as well as the possible involvement of this protein in the pathogenesis of the more aggressive forms of CLL. The overall frequency of p53 protein positivity in CLL was 15% (27 of 181 cases). There were no significant differences in age, sex, absolute lymphocyte count, or lymphocyte doubling time between p53-positive and -negative patients. By contrast, p53-positive patients had a significantly higher percentage of prolymphocytes (P = .002) and a significantly lower percentage of residual CD3-positive T lymphocytes (P = .0001). No correlation was found between the percentage of p53-positive cells and the percentage of cells in cycle assessed by the monoclonal antibody Ki-67. When the percentage of p53 positivity was correlated with the clinical stage of the disease, the proportion of p53-positive cases increased significantly from Binet's stage A (8 of 108; 7.4%), to stage B (12 of 49; 24.4%) and C (7 of 24; 29.2%) (P = .002). p53 positivity correlated also with the phase of the disease, showing a low expression at diagnosis (8 of 112; 7.1%) and a significantly higher expression in patients studied during the course of the disease (7 of 35; 20%) and, to a further extent, with disease progression (12 of 34; 35.3%) (P = .0001). The association of p53 protein expression with mutations in the gene was confirmed by direct sequence of the entire cDNA in 15 of the 17 ICC positive cases tested (88%). A significantly shorter treatment-free interval from diagnosis (P = .003) and a poorer response to therapy (P = .007) was observed in p53-positive compared with p53-negative patients. Overall survival from the time of diagnosis, as well as from the time of p53 protein analysis, was significantly shorter in patients with p53 protein expression (P = .03 and .0001, respectively). Moreover, in multivariate analysis, p53 expression and stage C were independently associated with a short survival. The results of this study indicate that in CLL the expression of the p53 protein, analyzed by a simple and reliable immunocytochemical method, is strongly associated with p53 gene mutations, a morphological variant (CLL with >10% prolymphocytes), advanced clinical stage, progressive disease, poor response to therapy, and short survival.

Tumor microvessel density, p53 expression, tumor size, and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma.

1994 ◽  
Vol 12 (3) ◽  
pp. 454-466 ◽  
Author(s):  
G Gasparini ◽  
N Weidner ◽  
P Bevilacqua ◽  
S Maluta ◽  
P Dalla Palma ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Breast Carcinoma ◽  
Protein Expression ◽  
Microvessel Density ◽  
Tumor Size ◽  
Lymphatic Vessel ◽  
P53 Protein ◽  
Univariate Analysis ◽  
P53 Expression ◽  
Node Negative

PURPOSE To determine the absolute and relative value of microvessel density (MVD), p53 and c-erbB-2 protein expression, peritumoral lymphatic vessel invasion (PLVI), and conventional prognosticators in predicting relapse-free (RFS) and overall survival (OS) rates in patients with node-negative breast carcinoma (NNBC). PATIENTS AND METHODS We monitored 254 consecutive patients with NNBC for a median of 62 months. Intratumoral MVD was measured after microvessels were immunostained using anti-CD31 antibody. p53 and c-erbB-2 protein and hormone receptors were also determined immunocytochemically. Results were analyzed by both univariate and multivariate statistical analysis. RESULTS Univariate analysis showed that MVD was significantly predictive of both RFS (odds ratio [OR], 8.30; P = .0001) and OS (OR, 4.50; P = .012) when tested as a continuous or dichotomous variable. Likewise, tumor size (OR, 3.16; P = .0012), PLVI (OR, 4.36; P = .0009), estrogen receptor (ER) status (OR, 2.35; P = .016), progesterone receptor (PR) status (OR, 2.00; P = .017), and expression of p53 protein (OR, 2.82; P = .004) were significantly associated with RFS. Tumor size (OR, 3.80; P = .0038) and expression of p53 protein (OR, 2.58; P = .024) were significantly associated with OS by univariate analysis. Multivariate analysis showed that MVD (P = .0004), p53 protein expression (P = .0063), tumor size (P = .0144), and PLVI (P = .0033) were all significant and independent prognostic factors for RFS. However, only tumor size (P = .004) and MVD (P = .047) were independent predictors for OS. c-erbB2 expression was not associated with outcome by either univariate or multivariate analysis. CONCLUSION MVD, p53 expression, PLVI, and tumor size are independent prognostic indicators of recurrence, which are useful in selection of high-risk NNBC patients who may be eligible to receive adjuvant therapies.

scholarly journals Immunohistochemical study of P53 protein expression in different prostate cancer Gleason grading groups

2020 ◽  
Vol 24 (2) ◽  
pp. 145-155 ◽  
Author(s):  
G. Y. Kudryavtsev ◽  
L. V. Kudryavtseva ◽  
L. M. Mikhaleva ◽  
Y. Y. Kudryavtseva ◽  
N. A. Solovyeva ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Proliferative Activity ◽  
Immunohistochemical Study ◽  
P53 Protein ◽  
Public Health Problem ◽  
Developed Countries ◽  
Ki 67 ◽  
P53 Expression ◽  
Gleason Grading ◽  
The Difference

Prostate cancer (PC) remains an urgent public health problem, especially in developed countries. The use of immunohistochemical research methods in addition to the morphological classification of prostate adenocarcinomas allows a more accurate diagnosis and prognosis of the disease. The aim of the study is to identify isoforms of P53 using clones of mouse antibodies (D-07 and Y5; Epitomics, USA) in prostate cancer with different proliferative activity and the degree of malignancy. Materials and Methods: The work included surgical material for prostate resection and prostatectomy, as well as biopsy specimens (56 cases in total). An immunohistochemical study was carried out with the Ki-67 marker, as well as with mouse monoclonal antibodies (D-07 and Y5) to the P53 protein, interacting with its wild and mutant isoforms. The significance of the difference in the samples was determined using the Mann-Whitney U-test, correlation relationships were determined using the Spearman coefficient. Results: Expression of P53 upon interaction with antibodies D-07 and Y5 was determined in 56.3% and 39.6%, respectively. A statistically significant direct correlation was found between the severity of P53 expression when interacting with Y5 antibodies and the degree of tumor differentiation (rs = 0.567, p 0.05), as well as between the expression level of this protein and tumor proliferative activity (rs = 0.698, p 0.05). Conclusion: Antibodies of clone D-07, interacting with both wild and mutant isoforms of P53 protein, show positive expression in adenocarcinomas of all degrees. Expression of the mutant P53 protein is most pronounced in low-differentiated carcinomas and correlates with high proliferative activity of tumor cells, which may be associated with a loss in the induction of P53-dependent apoptosis.

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