P53 Nuclear Overexpression Research Articles

HPV-negative Squamous Cell Carcinomas of the Cervix With Special Focus on Intraepithelial Precursor Lesions.

Recently, the World Health Organization (WHO) recognized human papilloma virus (HPV)-independent invasive cervical squamous cell carcinoma (SCC) without recognizing the existence of precursor lesions. This is a detailed characterization of 3 preinvasive lesions and 6 invasive SCC negative for HPV-DNA (32 genotypes), HPV-mRNA (14 genotypes) and genomic HPV sequencing. We evaluated histologic features, expression of p16ink4a, p53, CK7, and CK17, aberrations in 50 cancer genes and chromosomal copy number variations. HPV-negative preinvasive lesions were extensive basaloid or highly differentiated keratinizing intraepithelial proliferations of 3 to 20 cell layers thickness, partly with prominent cervical gland involvement. Overall, 2/3 intraepithelial lesions and the in situ component of 1/6 SCC showed p16ink4a block staining, while 1/6 in situ component revealed heterogenous p16ink4a staining. All invasive components of keratinizing SCC were p16ink4a-negative. Preinvasive and invasive SCC showed inconsistent CK7 and CK17 staining. Nuclear p53 overexpression was restricted to the TP53 gene mutated SCC. The highly vascularized peritumoral stroma showed a dense inflammatory infiltrate including plasma cells and intratumoral and peritumoral eosinophilic granulocytes. Inconsistent somatic gene mutations (PIK3CA, STK11, TP53, SMARC2B, and GNAS) occurred predominantly in nonhotspot locations at low mutational frequency in 3/6 SCC. Consistent aberrations included the pathogenic (angiogenic) germline polymorphism Q472H in the KDR gene (7/9 patients), and chromosome 3q gains (4/9 patients). In conclusion, HPV-negative intraepithelial cervical precancerous lesions exist, either as highly differentiated keratinized intraepithelial proliferations reminiscent of differentiated vulvar intraepithelial neoplasia, or undifferentiated basaloid intraepithelial lesions with occasional p16ink4a block staining resembling high-grade squamous intraepithelial lesion. Gains of chromosome 3q, angiogenic germline variants the inflammatory infiltrate may contribute to progression of HPV-negative cervical carcinogenesis.

Clinicopathological factors associated with BRAF-V600E mutation in colorectal serrated adenomas.

Serrated adenomas are genetically heterogeneous, and the histological classification into sessile serrated (SSA) adenoma and traditional serrated adenoma (TSA) does not reflect the molecular landscape. The objective of this study was to assess clinical or pathological factors associated with BRAF-V600E mutation in serrated adenomas. Systematic review and meta-analysis was performed by searching electronic databases from January 2011 to January 2019 for studies assessing the association of BRAF-V600E mutation with clinical or pathological features of serrated adenomas. Odds ratio (OR) was calculated for each factor; a P-value <0.05 was considered significant. Forty studies assessing 3511 serrated adenomas (2375 SSAs and 1136 TSAs) were included. BRAF-V600E mutation was significantly associated with proximal localisation (OR = 2.71; P < 0.00001) and CIMP-H status (OR = 4.81; P < 0.0001) in both SSA and TSA, with polyp size <10 mm (OR = 0.41; P = 0.02) in TSA, and with endoscopic pit pattern II-O (OR = 13.11; P < 0.00001) and expression of MUC5A5 (OR = 4.43; P = 0.003) and MUC6 (OR = 2.28; P < 0.05) in SSA. Conversely, BRAF mutation was not associated with age <70 years (OR = 1.63; P = 0.34), age <60 years (OR = 0.86; P = 0.79), female sex (OR = 0.77; P = 0.12), flat morphology (OR = 1.52; P = 0.16), presence of any dysplasia (OR = 1.01; P = 0.59), serrated dysplasia (OR = 1.23; P = 0.72) and invasive cancer (OR = 0.67; P = 0.32), nuclear β-catenin expression (OR = 0.73; P = 0.21) and p53 overexpression (OR = 1.24; P = 0.82). In conclusion, BRAF-V600E mutation is associated with proximal localisation and CIMP-H status in both SSA and TSA, with size <10 mm only in TSA, and with expression of MUC5A5 and MUC6 and endoscopic pit pattern II-O at least in SSA. In serrated adenomas, BRAF-V600E mutation does not seem to be associated with age and sex, with the prevalence of dysplasia and cancer and with the morphology of the dysplastic component.

Abstract P5-05-11: Clinical significance of androgen receptor expression in breast cancer

Abstract Background Breast cancer is highly heterogeneous and immunohistochemistry (IHC) is used to determine breast cancer subtypes using estrogen and progesterone receptor (ER and PgR), HER2 and Ki-67. The androgen receptor (AR) is frequently expressed in breast cancer, but evaluation of AR has not been standardized and the oncogenic activity in breast cancer is still unclear. The objectives of this study were to assess the clinical significance of AR expression in breast cancer patients with primary (pretreatment and posttreatment) and recurrent breast cancer in relation to breast cancer subtype. Methods Primary and recurrent breast cancer patients who underwent treatment from March 2017 to May 2018 were enrolled in this study. A total of 591 primary breast cancer cases and 52 recurrent cases were analyzed. Thirty-four primary cases received treatment before surgery. The factors investigated included nodal status, tumor size, nuclear grade, ER/PgR and HER2 status, p53 overexpression, and the Ki-67 index value. The AR expression was evaluated using IHC and the expression was divided into 3 groups; negative, low (&amp;lt;10%) and high (≥10%). Breast cancer subtypes were categorized based on the IHC data derived from ER/PgR, HER2 and Ki-67 (cutoff point: 20%) in invasive tumors. Results The AR expression rates were 69.7%(low: 33.9% and high: 35.8%)in all primary cases. Patients who received treatment before surgery had an AR rate of 38.2% which was significantly different from the untreated cases (p=0.002). In the cases with neoadjuvant chemotherapy, the positive rate significantly decreased after chemotherapy in the cases with non-pCR (pathological complete response). The positive rate of recurrent/metastatic cases was 57.7% (low: 34.6% and high: 23.1%). Higher AR expression significantly correlated with smaller tumor size, positive ER/PgR, lower Ki-67 values and nuclear grade and negative p53 overexpression. The AR expression rate was 72.5% in Luminal A, 73.2% in Luminal B, 80% in Luminal HER2, 56.8% in HER2 enriched and 43.5% in triple negative (TN) cases. Moreover, in the TN tumor cases, AR expression significantly correlated with postmenopausal status and a higher degree of malignancy determined by Ki-67, p53, and nuclear grade. However, there was no significant relationship between these factors and the other subtypes. Conclusion The AR expressions were higher in the primary breast cancer cases than in the pretreated and recurrent cases. The AR expression significantly correlated with a lower degree of malignancy and postmenopausal status only in the TN breast cancer cases. These findings suggest that the TN cases with AR-positive tumors have a more favorable prognosis compared with the cases with AR-negative tumors. However, further studies are needed to determine the predictive and prognostic factors for clinical use. Citation Format: Arima N, Nishimura R, Osako T, Okumura Y, Nakano M, Fujisue M. Clinical significance of androgen receptor expression in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-11.

Prognostic role of SIRT1 in hepatocellular carcinoma.

To determine the clinical significance of silent mating type information regulation 2 homolog 1 (SIRT1) expression in Hepatocellular Carcinoma (HCC) and its association with P53 and Yes-associated protein 2 (YAP2) expression. Observational study. Department of General Surgery, China-Japan Union Hospital of Jilin University, Changchun, China, from January 2000 to January 2010. Tissue microarray technique and immunohistochemistry were conducted to detect the expression of SIRT1, P53 and YAP2 proteins in 300 self-paired HCC samples. Associations with clinicopathologic manifestations were analyzed, overall survival analysis and multivariate analysis were performed. By tissue microarray technique and immunohistochemistry on 300 self-paired HCC samples, it was found that SIRT1, P53 and YAP2 were significantly overexpressed in HCC tumor tissues compared with adjacent non-tumor tissues. SIRT1 immunostaining localized both in the nucleus (145/300, 48.3%) and the cytoplasm (70/300, 23.3%), and the overexpression of nuclear SIRT1 was positively related to the overexpression of P53 and YAP2. Survival analysis showed that nuclear SIRT1, P53 and YAP2 overexpression predicted poor overall survival while cytoplasmic SIRT1 overexpression predicted longer overall survival. Multivariate analysis showed nuclear SIRT1 and P53 overexpression as independent tumor promoters while cytoplasmic SIRT1 overexpression as an independent tumor suppressor. SIRT1 was overexpressed in HCC and the expression was positively related to P53 and YAP2 expression. As the nuclear SIRT1 functions as a tumor promoter and cytoplasmic SIRT1 functions as a tumor suppressor, the role of SIRT1 in HCC should be reconsidered.

Clinical Significance of CK19 Negative Breast Cancer

Analysis of sentinel lymph nodes (SLNs) by means of One-Step Nucleic Acid Amplification (OSNA) is gaining widespread use as a quick and accurate method. This assay detects the expression level of cytokeratin 19 (CK19) which is present in some but not all breast tumors. In this study, the clinical significance of negative CK19 was investigated in 219 cases of primary breast cancer. In 179 patients with clinically negative nodes, OSNA and imprint smear cytology of SLN were performed simultaneously. The OSNA revealed a node-positive rate of 24.6%. Negative CK19 correlated significantly with negative ER/PgR and higher Ki-67 values, and marginally with higher nuclear grade and p53 overexpression. The triple negative subtype showed lower CK19 expression. OSNA revealed that one of the negative CK19 cases was actually a false negative but this was corrected with the use of the imprint smear cytology. In conclusion, CK19 negativity reflected the aggressiveness of primary breast cancer. OSNA assay used to analyze SLN was useful, but there is a possibility that it will mistakenly detect false negatives in CK19 negative tumors. Therefore, in tumors with negative CK19, the imprint smear cytology may be more useful in cases with macrometastasis.

The hormone receptor, human epidermal growth factor receptor 2, and molecular subtype status of individual tumor foci in multifocal/multicentric invasive ductal carcinoma of breast

Multifocal/multicentric breast cancers are common. However, investigations of biomarkers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 in individual tumor foci of such cancers are rare. This study was designed to evaluate the status of the hormone receptors, human epidermal growth factor receptor 2, and its molecular subtypes in individual foci of multifocal/multicentric invasive ductal carcinoma of the breast and to identify the factors associated with the different phenotypes of individual foci. We performed immunohistochemical analyses of the estrogen receptor, progesterone receptor, cytokeratin 5/6, epidermal growth factor receptor, and p53 and fluorescence in situ hybridization of human epidermal growth factor receptor 2 in individual foci of 65 cases of multifocal/multicentric invasive ductal carcinoma and the associated ductal carcinoma in situ components using tissue microarrays. The estrogen receptor status differed in 2 (3%) of the 65 invasive ductal carcinomas, progesterone receptor status in 7 (11%), human epidermal growth factor receptor 2 status in 4 (6%), and molecular subtypes in 5 (8%). The presence of different molecular subtypes in the invasive tumor foci was associated with differences in histologic features (P = .005), high histologic and nuclear grade (P = .012 and P = .021, respectively), p53 overexpression (P = .006), and mixed molecular subtypes in the ductal carcinoma in situ components (P = .011). Multifocal/multicentric invasive ductal carcinomas usually have a single phenotype in terms of hormone receptors, human epidermal growth factor receptor 2, and molecular subtypes; and thus, immunohistochemical analyses of the index tumor may be sufficient in routine practice. However, if multifocal/multicentric invasive ductal carcinomas are of high grade, of different histologic features, or of heterogeneous ductal carcinoma in situ component, biomarkers of the various foci need to be evaluated separately.

978 PENILE CANCER BIOMARKERS IN MEN WITH LICHEN SCLEROSUS

You have accessJournal of UrologyPenis/Testis/Urethra: Benign & Malignant Disease1 Apr 2011978 PENILE CANCER BIOMARKERS IN MEN WITH LICHEN SCLEROSUS Joshua Meeks, Tao Qi, Shreenath Bishu, chris gonzalez, and Ximing Yang Joshua MeeksJoshua Meeks Chicago, IL More articles by this author , Tao QiTao Qi Chicago, IL More articles by this author , Shreenath BishuShreenath Bishu Chicago, IL More articles by this author , chris gonzalezchris gonzalez Chicago, IL More articles by this author , and Ximing YangXiming Yang Chicago, IL More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.989AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Lichen sclerosus (LS) is an inflammatory disorder that affects the genital skin and urethra of men. Rare cases of LS can undergo malignant transformation and result in penile carcinoma. The relationship between LS and squamous cell cancer (SCCA) of the penis remain unclear and LS may be a premalignant state. In order to evaluate if LS is associated with cytological changes that occur in SCCA of the penis, we performed immunohistochemical analysis of tissues from men with LS. METHODS Tissue from men that underwent urethroplasty, penile biopsy or circumcision were subjected to immunohistochemistry specific for the tumor suppressors p53, p16, and the proliferative marker Ki67. Immunostains were semiquantitated and compared to those of penile squamous cell carcinoma by genitourinary pathologists. RESULTS A total of 38 men had a histological diagnosis of LS. Urethral strictures were found in 12 of 38 cases (32%). Chronic non-specific inflammation was found in 26/38 (68%) cases, while the remaining 32% demonstrated sclerotic fibrosis. Nuclear overexpression of p53, a tumor suppressor gene upregulated in cancer, was found in only 10(26%) of LS tissues. The cell-cycle regulating tumor suppressor p16, a target of the human papilloma virus oncoprotein E7, was upregulated at low levels in 27 patients (71%) and high levels in 5(13%). In addition to the high level of p53 and p16 immunoreactivitiy, penile SCCA demonstrated a high level of cellular proliferation by high Ki67 reactivity. Tissue from LS patients had relatively little proliferative activity with 23 patients demonstrating weak or focal staining (60%) and only 5 (13%) expressing strong nuclear Ki67 staining. CONCLUSIONS Based on histologic and immunohistochemical profiles, LS can be divided into two groups that may represent early (inflammatory) and late (sclerosing) phases of the disease or different risk groups for penile cancer development. A subset of patients in the inflammatory group shared similarities to penile squamous cell carcinoma by immunostaining, while the majority of LS showed low proliferative activity and negativity for p53 and p16, which does not suggesting a pre-malignant lesion. These markers may be useful in patients with LS for evaluation of their risks for developing squamous cell carcinoma. Future prospective studies are needed to determine the predictive value of these biomarkers in men with LS. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e394 Peer Review Report Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joshua Meeks Chicago, IL More articles by this author Tao Qi Chicago, IL More articles by this author Shreenath Bishu Chicago, IL More articles by this author chris gonzalez Chicago, IL More articles by this author Ximing Yang Chicago, IL More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Nuclear Overexpression of Mitotic Regulatory Proteins in Biliary Tract Cancer: Correlation with Clinicopathologic Features and Patient Survival

Mitosis dysregulation is common in cancers. This study explored the nuclear expression patterns and prognostic significance of mitotic regulatory proteins, including Aurora kinases, survivin, and p53, in biliary tract cancer (BTC). Archival tumor samples from 161 BTC patients who underwent surgery were tested for the expression of Aurora-A, Aurora-B, survivin, and p53 by immunohistochemistry. The potential endogeneity among the clinicopathologic variables and survival outcome was assessed by a generalized simultaneous equations model. Nuclear overexpression of Aurora-A, Aurora-B, survivin, and p53 was found in 79 (49.1%), 45 (28.0%), 55 (34.2%), and 55 (34.2%) patients, respectively. Intrahepatic cholangiocarcinoma, compared with the other two subtypes, had significantly higher proportions of nuclear overexpression of Aurora-B and survivin (37.8% and 47.3%, respectively). Simultaneous overexpression of Aurora-A and Aurora-B was correlated with that of p53. Overexpression of Aurora-B was also correlated with that of survivin and tumor grade. Our data indicate that simultaneous overexpression of Aurora-A and Aurora-B, suggesting dysregulated mitosis is associated with worse survival in patients with BTC. Independent prognostic factors for poor overall survival included simultaneous overexpression of Aurora-A and Aurora-B (hazard ratio, 1.997; 95% confidence interval, 1.239-3.219; P = 0.0045) and tumor grade (hazard ratio, 2.117; 95% confidence interval, 1.339-3.348; P = 0.0013) assessed by a multivariate analysis stratified by American Joint Committee on Cancer stage and p53 overexpression. Endogeneity testing suggested that nuclear overexpression of p53 and tumor type may influence patient survival through their interactions with Aurora-A/Aurora-B expression and tumor grade.

Focal adhesion kinase overexpression in breast cancer molecular subtypes.

Abstract Abstract #1091 Focal adhesion kinase (FAK) is a protein tyrosine kinase which regulates multiple cellular processes including growth, differentiation, adhesion, motility and apoptosis and is a critical mediator of signalling events between cells and their extracellular matrix.&amp;#x2028; FAK is highly expressed in invasive breast cancer (BC) where its upregulation has been implicated in the acquisition of an invasive tumor phenotype. Hierarchical cluster analysis identified subgroups of BC with separate gene expression profiles which detect four main tumor phenotypes, Luminal A (LA), Luminal B (LB), Basal-like (B), and HER2 subtype (HS) characterized by significant differences in prognosis. Up to now, there are no data concerning FAK distribution within the molecular BC subtypes. In this study FAK overexpression was evaluated, by immunohistochemistry (IHC), in a retrospective series of 193 invasive BC surgically treated at our Institution between 2002 and 2005. Associations with conventional pathological factors and with molecular subtypes were analyzed by Multiple Correspondence Analysis (MCA) and chi square test, aimed to determine the impact of FAK high positivity within BC molecular subtypes and to define a biologic profile associated to aggressive bio-pathologic variables such as tumor size (T), nodal status (N), grading (G), p53, Bcl2, Ki-67, p-AKT, p-MAPK . The anti-FAK 4.47 monoclonal antibody was used to detected FAK expression which was scored as high (2 or 3 intensity and ≥ 90% positive cells) or low (0 or 1 intensity and &amp;lt; 90% positive cells).&amp;#x2028; FAK was overexpressed in 41.7% of LA, 70% of LB, in 48.0% of HER2 subtype and 52.2% of Basal-like BC. The relationships among the bio-pathological factors, analysed by MCA, showed that FAK+ is located in the quadrant containing more aggressive tumor phenotypes such as HER2 and Basal like subtypes together with T3-4, N+, G3 and p53+, high Ki67, Bcl2–, p-MAPK+, p-AKT+. Moreover, in LA tumors, FAK overexpression is significantly related to nodal status (p=0.05), grading (p=0.007), p53 nuclear accumulation (p=0.047) and p-AKT overexpression (p=0.001) and it appears to be a useful tool in identifying BC patients at higher risk of progression.&amp;#x2028; The presence of FAK upregulation in LA subtype, may represent a useful tool in identifying those LA patients who would benefit from more aggressive adjuvant therapy. In this context, further investigations are necessary to better assess the prognostic role of FAK overexpression in low risk BC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1091.

Differential expression of two new members of the p53 family, p63 and p73, in extramammary Paget’s disease

The proteins p53, p63 and p73 are known to be overexpressed and to play important roles in the pathogenesis of many tumours, but the expression of p63 and p73 has not previously been investigated in extramammary Paget's disease (EMPD). To investigate the potential contribution of p53, p63 and p73 in the pathogenesis of EMPD. In total, 35 paraffin wax-embedded tissue samples from patients with EMPD were examined using immunohistochemical staining for p53, p63 and p73. All of the 35 EMPD specimens, including all 6 invasive EMPD and 2 metastatic lymph-node specimens, showed nuclear overexpression of both p53 and p73. The expression levels (percentage of positive cells) of p53 and p73 (90.66 +/- 12.53% and 80.20 +/- 13.07%) in EMPD were significantly higher than those of normal skin. There was a significant correlation between the expression levels of p53 and p73 in EMPD. In 29 of 35 EMPD specimens, there was no nuclear expression of p63, and weak or moderate staining was found in only 6 specimens. The expression level of p63 in EMPD was significantly less than that in normal skin. Our study shows that the concordant overexpression of p53 and p73 and the decreased expression of p63 may play a pivotal role in the pathogenesis of EMPD. The decreased expression of p63 may play a more important role in the pathogenesis of EMPD than the overexpression of p53 and p73.

Biological markers of cisplatin resistance in advanced testicular germ cell tumors (GCT)

16063 Background: GCT of the testis show exquisite sensitivity to treatment with cisplatin. Despite the high cure rates provided by platinum-based chemotherapy, 10–20% of patients (pts) die from progressive disease. Although various cellular pathways may influence cisplatin efficacy, their actual impact has not been comprehensively investigated in tumor samples from advanced subgroups of testicular GCT. In order to define a novel molecular profile of treatment response and cisplatin resistance in GCT, we here immunohistochemically assessed the expression status of proteins in the Rb and p53 tumor suppressor pathways including p53, MDM2, and G1-phase Cyclins D1 and D2 (CD1 and CD2) in advanced testicular cancer and correlated the results with the clinical course. Methods: Paraffin-embedded tumor tissues from 84 pts with advanced GCT treated with cisplatin-based chemotherapy from 1980 to 2003 were analyzed. The immunoreactivity of p53, MDM2, CD1 and CD2 was scored according to the percentage of stained nuclei per total number of nuclei in the sample preparation. The cut-off values for tumor cell staining were defined as follows: p53 nuclear overexpression if ≥ 10% tumor nuclei stained; MDM2 overexpression if > 40% tumor nuclei stained; any trace of staining was scored as positive for CD1 expression and CD2 overexpression was considered if ≥ 5% tumor nuclei stained. Statistical analyses were performed to evaluate both the predictive and the prognostic impact of each molecular marker. Results: The percentages of positive expression of p53, MDM2, CD1 and CD2 were 56, 57, 37.5 and 55%, respectively. From univariate analysis, positive CD2 expression was found to be marginally associated with shorter median duration of progression-free survival (p = 0.06). In multivariate analysis, CD2 overexpression no longer retained statistical significance with treatment response nor survival. Conclusions: Aberrant CD2 expression, a previously described early-event in germ cell tumorigenesis, appears to further determine a shorter progression-free survival in patients with advanced GCT. Further larger studies are required to validate the selective usage of the D-Type Cyclin CD2 during acquisition of cisplatin resistance by GCT. No significant financial relationships to disclose.

Is triple negative a prognostic factor in breast cancer?

Breast cancer is characterized by hormone dependency, and endocrine therapy is a key treatment in breast cancer. Recently, targeted therapies such as Trastuzumab treatment for HER2-positive breast cancer has been important. Triple-negative (TN) breast cancer is characterized by lack of expression of estrogen receptor (ER) and progesterone receptor (PgR), and the absence of HER2 protein overexpression, and so there is no targeted therapy for this subtype. In this study, we examined the biological and prognostic characteristics in TN breast cancer. Between January 1998 and September 2006, 1,552 patients with primary breast cancer were investigated retrospectively in this study and ER, PgR and HER2 status were evaluated in all cases. Furthermore, p53 overexpression and Ki67 values were examined immunohistochemically. Patient distribution according to ER, PgR or HER2 status was as follows: ER and PgR positive: 57.9%, and ER and PgR negative: 25.1%. With regards to the HER2 status, HER2 positive was 23.3%, and triple negative (TN) was 14.0%. TN breast cancer has a high proliferation rate, high nuclear grade and frequent p53 overexpression. Patients with TN tumors had a significantly poorer disease-free survival (DFS) than those with non-TN tumors. After recurrence the overall survival (OS) rate in TN cases was significantly lower than that of the non-TN cases. Multivariate analysis revealed that TN was a significant factor for DFS and OS after recurrence. TN breast cancer is a rare subtype with a high proliferation rate and a high nuclear grade, p53 overexpression, and lower DFS/OS. To improve the prognosis of TN breast cancer, a new effective strategy needs to be developed.

P53/MDM2 overexpression in metastatic endometrial cancer: correlation with clinicopathological features and patient outcome

Several studies have reported that p53/mdm2 distortions play a pivotal role in the development and progression of various human malignancies. However, the number of reports having evaluated simultaneously the components of the P53-pathway alterations in advanced-stage human endometrial carcinomas (EC) is low. In this study, we examined the expression of P53/MDM2 proteins in primary and metastatic ECs, and analyzed the clinicopathological characteristics as well as the survival outcome of patients in relation to P53/MDM2 overexpression. The study group comprised 36 patients with advanced EC, whose primary and metastatic tumor slides were sufficient for analysis. Immunohistochemical assessment was made by applying anti-human P53 and MDM2 antibodies and a highly sensitive EnVision(+)/HPR visualization system. Nuclear P53 overexpression was seen in 11 (31%) primary ECs and 12 (33%) metastatic tumors. There was a significant correlation between P53 overexpression (in primary cancers and metastatic tumors) and MDM2 overexpression in metastatic tumors. Nuclear MDM2 overexpression was noted in 42% (15/36) of primary carcinomas and in 47% (17/36) of metastatic tumors. A significant association existed between MDM2 overexpression and histological grading (G1 + G2 versus G3, P = 0.043). P53/MDM2 overexpression occurred simultaneously in 7 out of 36 (19%) primary ECs and in 9 out of 36 (25%) metastatic lesions. Concomitant overexpression of these proteins was reported in 7 out of 36 (19%) cases and tended to be higher in tumors showing VSI compared to neoplasms lacking vascular space invasion (P = 0.051). P53 overexpression, either in primary ECs (P < 0.0001) or metastatic lesions (P < 0.0001), was significantly associated with poor survival in univariate analysis. Moreover, the log-rank test demonstrated that simultaneous P53/MDM2 overexpression was also correlated with decreased length of survival. There was no correlation between MDM2 overexpression and patient survival. Multivariate Cox regression analysis revealed that only P53 overexpression is an independent predictor of survival. In conclusion, our data support the view that patients with P53 overexpression are significantly associated with an unfavorable outcome, whereas MDM2 overexpression is not related to decreased survival length in women operated on for advanced-stage EC.

Expression of p53 protein in malignant melanoma: clinicopathological and prognostic implications.

In the present study, we investigated the expression of the tumour suppressor protein p53 in 113 primary and 43 metastatic malignant melanomas by immunohistochemistry, and correlated the findings with clinicopathological parameters such as histological melanoma subtype, thickness of primary melanomas (Breslow thickness) and patient outcome. In primary melanomas, the polyclonal anti-p53 antibody CM-1 detected immunoreactivity in 70% of the lesions, predominantly in the cytoplasm. Signals were observed in this cellular compartment in 57% of the melanomas, whereas in 32% nuclear p53 over-expression was detected. Immunohistochemistry, using the monoclonal antibody DO-1, revealed lower staining frequencies. However, both antibodies showed congruent results in approximately 80% of the cases. Overall, immunoreactivity was observed in 73% of superficial spreading melanomas, but only in 52% of lentigo maligna melanomas. This difference (P < 0.001) was mainly due to a lower frequency of cytoplasmic immunoreactivity (P < 0.002). There was no difference with respect to cytoplasmic and nuclear immunoreactivity between thin (< 1 mm thickness) and thicker primary melanomas. Staining frequencies detected in metastatic lesions seemed to be lower than in primary tumours. In 103 primary melanomas, follow-up data for at least 5 years were available. In 71% (54 of 76) of the primary melanomas which did not recur, and in 78% (21 of 27) of tumours with subsequent metastases, p53 over-expression was detected by CM-1. However, this difference was not statistically significant. The results of the present study indicate that immunoreactivity to anti-p53 antibodies is a common observation in malignant melanomas, with staining signals predominantly found in the cytoplasm of cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunohistochemical Detection of Mdm2 and p53 in Feline Mammary Gland Tumors

The objective of this study was to evaluate nuclear reactivity of Mdm2 and p53 proteins by immunohistochemical means in feline mammary gland tumors; 12 adenomas which included 6 adenomatous lesions obtained from the tissue adjacent to adenocarcinomas, and 22 adenocarcinomas. Seven adenomas and 18 adenocarcinomas showed moderate or marked Mdm2 reactivity. Sixteen adenocarcinomas showed moderate to marked p53 reactivity, but 9 adenomas showed none. Discordant Mdm2 overexpression was found in 5 adenomas and 3 adenocarcinomas, although co-overexpression of Mdm2 and p53 was found in 15 adenocarcinomas. These results suggest that nuclear overexpression of Mdm2 is present in the tumors of early stage without p53 overexpression and related to feline mammary gland tumorigenesis. Nuclear overexpression of p53 is more frequent in adenocarcinomas, but not in adenomas.

Assessment of the Transcriptional Activity of p53 Improves the Prediction of Recurrence in Superficial Transitional Cell Carcinoma of the Bladder

To investigate the value of p53 functional analysis of separated alleles in yeast (FASAY) as a witness of p53/p21 pathway alteration and as a predictor of recurrence in superficial transitional cell carcinomas. p53 transcriptional activity was prospectively analyzed in 52 newly diagnosed transitional cell carcinoma using FASAY competent for the transactivation of p21 and bax promoters. TP53 and p21 gene expression was quantified by real-time PCR, and expression of corresponding proteins was assessed by immunohistochemistry. In addition to tumor stage and grade, the predictive value of FASAY, real-time PCR, and immunohistochemistry for tumor recurrence was assessed by Cox survival analysis. A total (p21 and bax) or partial (bax only) loss of transcriptional activity was observed in 15 of 52 (29%) and 4 of 52 (7.7%) cases, respectively, a partial loss being consistently associated with R283H mutation. p53 nuclear overexpression grossly overestimated (approximately 40%) or underestimated (approximately 10%) the true incidence of p53 transcriptional abnormalities, especially in Ta-T1 grade 1 to 2 tumors. Loss of p21 transactivation significantly correlated with decreased p21 gene expression and lack of expression of p21 (P = 0.001). FASAY had a better predictive value for recurrence than p53 immunohistochemistry (Cox hazard ratio, 6.57 versus 3.95; P = 0.0002 versus 0.019, respectively), whereas neither p21 immunohistochemistry (hazard ratio, 1.9; P = 0.29) nor TP53 or p21 gene expression were significant predictors of recurrence. The prognostic difference between FASAY and p53 immunohistochemistry was maintained in the subgroup of Ta-T1 grade 3 tumors. FASAY is a valuable surrogate marker for assessing p53/p21 pathway alteration and predicts transitional cell carcinoma recurrence better than p53 immunohistochemistry.

P53 status and response to radiotherapy in rectal cancer: a prospective multilevel analysis

The aim of this study was to evaluate, in a prospective study, the predictive role of p53 status analysed at four different levels in identifying the response to preoperative radiotherapy in rectal adenocarcinoma. Before treatment, 70 patients were staged and endoscopic forceps biopsies from the tumour area were taken. p53 status was assessed by total cDNA sequencing, allelic loss analysis, immunohistochemistry, and p53 antibodies. Neoadjuvant treatment was based on preoperative radiotherapy or radiochemotherapy. Response to therapy was evaluated after surgery by both pathologic downstaging and histologic tumour regression grade. In all, 35 patients (50.0%) had p53 gene mutations; 44.4% of patients had an allelic loss; nuclear p53 overexpression was observed in 39 patients (55.7%); and p53 antibodies were detected in 11 patients (16.7%). In the multilevel analysis of p53 status, gene mutations correlated with both nuclear protein overexpression (P<0.0001) and loss of heterozygosity (P=0.013). In all, 29 patients (41.4%) were downstaged by pathologic analysis, and 19 patients (29.2%) were classified as tumour regression grade 1. Whatever the method of evaluation of treatment response, no correlation between p53 alterations and response to radiotherapy was observed. Our results do not support the use of p53 alterations alone as a predictive marker for response to radiotherapy in rectal carcinoma.

APOPTOSIS AND CHEMOTHERAPY FOR BLADDER CANCER

We discuss the role of apoptosis, that is gene directed self-destruction of a cell, in the response of bladder transitional cell carcinoma cells to chemotherapy. A directed MEDLINE literature search of apoptosis, bladder cancer and chemotherapy was performed to extract relevant information for review. The characteristics of apoptotic cells were defined and the methods in common use to detect these traits is described. The role of the key mediators of the apoptotic process in bladder cancer is discussed in the context of chemosensitivity and disease stage. The importance of the apoptosis induction after chemotherapy is highlighted. On stimulus by appropriate external or internal signals a cell may alter the expression of genes encoding for proteins associated with the apoptotic process. The development of apoptosis depends on the balance between pro-apoptotic and anti-apoptotic proteins. Key alterations in genes and proteins related to apoptosis within bladder cancer result in a shift away from the default state of apoptosis toward a cell with increased survival properties that is chemoresistant. Much current research in bladder cancer is aimed at restoring chemosensitivity by shifting the cell toward a pro-apoptotic phenotype. Successful translation of this work into clinical practice may improve survival in patients in whom prognosis is currently poor.

Prognostic Value of PCNA and Mutant p53 Expression in Laryngeal Squamous Cell Carcinoma

The objective of this study was to investigate the prognostic significance of p53, and proliferative cell nuclear antigen (PCNA) in laryngeal squamous cell carcinoma (LSCC). Sixty pathologic specimens from the patients with LSCC were examined for the expression of the p53 and PCNA, with complete follow-up data. Sixty-three percent of the cases displayed nuclear p53 overexpression. There was a correlation between p53 overexpression and histological grades (p = 0.03), and localization site (p = 0.05). Median of PCNA index was 42.2 (range 5.9 to 85.2). There was no difference between the p53 overexpression group and the normal group in proliferative activity determined by PCNA (p = 0.73). In univariate analyses, localization site, grade, stage, invasion pattern, lymph node status, were significant factors in estimating disease free survival (DFS). Grade was the most important factor affecting recurrence (p = 0.002). In multivariate analyses, grade was the only significant predictor for DFS (p = 0.001). Grade (p = 0.001) and invasion pattern (p = 0.03) were found to be significant predictors of overall survival. In conclusion, the histological grade was the most reliable important prognostic factor. Further studies are necessary to facilitate understanding of the mechanisms of laryngeal carcinogenesis.

Pretreatment p53 nuclear overexpression as a prognostic marker in superficial bladder cancer treated with Bacillus Calmette-Guérin (BCG).

Altered p53 gene product correlates with the stage and grade of bladder tumor, but its value as a predictor of BCG response has been disappointing. In order to revisit the prognostic value of pretreatment p53 nuclear overexpression for the BCG response, we studied a large cohort of consecutive patients with superficial bladder cancer treated with BCG. From 1988 to 2001, 102 patients with a history of multifocal, recurrent, and/or high-risk papillary transitional cell carcinoma or carcinoma in situ, were treated for the first time with BCG. p53 immunostaining was performed on paraffin-embedded tissues using monoclonal antibody DO7 and an automated immunostainer. Special attention was paid to the conditions of tumor fixation. p53 overexpression was defined as more than 20% tumor cells with p53-stained nuclei. Immunostaining was significantly higher for Ta/T1 G3 +/- Cis (p < 0.001), tumoral substage T1b (p = 0.001), grade 3 (p = 0.0001), and Cis (p = 0.002). Times to recurrence, progression and cancer death were shorter among patients with p53 overexpression (p = 0.03; p < 0.0001; p = 0.0003). In multivariate analysis, p53 overexpression was an independent predictor of recurrence (p = 0.0003) [RR = 0.15; 95%CI, 0.06 to 0.42]. Pretreatment p53 nuclear overexpression in superficial bladder tumors is associated with a high risk of disease recurrence, progression and cancer death after BCG therapy. Applying antibody DO7 with an automated immunostainer and stringent fixative conditions, p53 nuclear immunostaining yields clinically relevant information and may be a useful tool for selecting patients with superficial bladder cancer who might be resistant to BCG.