Positive P53 Expression Research Articles

The significance of Wilms Tumor Gene (WT1) and p53 expression in curettage specimens of patients with endometrial carcinomas

In this retrospective experimental study, we assessed the immunohistochemical expression of Wilms Tumor Gene (WT1) and p53 in endometrial biopsies of patients with endometrial cancer, and correlated their expression with the final pathological findings.Sixty-two patients with primary endometrial cancer who underwent surgical treatment were investigated.Immunohistochemical expression of Wilms Tumor Gene (WT1) and p53 was assessed in curettage specimens, and the final pathology reports from hysterectomy specimens were reviewed.The expression of these markers seems to play a role in curettage specimens as they correlate with the final tumor characteristics of hysterectomy specimens.Five out of sixty-two endometrial cancer specimens (8.1%) were WT1-positive, and 21 specimens (33.9%) were P53-positive. Positive expression of WT1 and P53 was significantly associated with the non-endometrioid type (p value of 0.019 and 0.005, respectively). Positive WT1 expression was significantly associated with high grade lesions, deep myometrial invasion, and advanced stage disease. Moreover, a statistically significant inverse relationship was observed between the positivity of WT1 and P53, and the positivity of ER and PR.We think that examination for WT1 and p53 in curettage specimens might help to predict the final pathological diagnosis in patients with endometrial cancer. This might be useful for the identification of high risk groups and, therefore, of candidates for more radical surgery.

Different expression pattern and significance of p14ARF-Mdm2-p53 pathway and Bmi-1 exist between gastric cardia and distal gastric adenocarcinoma

Recent studies have suggested that adenocarcinoma of gastric cardia (GCA) is distinct from distal stomach, with different risk factors, tumor characteristics, and biological behavior. The aim of this study is to evaluate the possible difference in the expressions of p14ARF, Mdm2, p53, and Bmi-1 by immunohistochemical staining on paraffin-embedded tissues of gastric cardia adenocarcinoma (GCA; n = 74) and distal gastric adenocarcinoma (DGA; n = 41). The results showed that the percentage of p14ARF-negative expression, Mdm2 overexpression, p53-positive expression, and p53 pathway abnormality (p14ARF(-)/Mdm2(+)/p53(+)) were all significantly higher in GCA than those in DGA (P < .05). Further analysis showed that in GCA, the negative expression of p14ARF was significantly associated with poor differentiation, Mdm2 overexpression with tumor stage and lymph node metastasis, and positive p53 expression with tumor stage (P < .05), whereas in DGA, only Mdm2 overexpression was related with well/moderate differentiation (P < .05). Abnormality of the p53 pathway was significantly correlated with poorer differentiation only in GCA (P < .05). The positive expression of Bmi-1 in all cases of GCA and DGA was significantly higher than normal gastric mucosa epithelium, but no difference was found between GCA and DGA (P > .05). Thus, the results in this study confirmed that different expression pattern and clinicopathologic significance of the p14ARF-Mdm2-p53 pathway did exist between GCA and DGA. The results further support the hypothesis that different mechanisms may be involved in the development and progression of adenocarcinoma from cardia and distal portion of stomach.

P53 expression in synovial sarcoma and its association with prognostic factors

Background: Synovial sarcoma is an aggressive tumor and has two common histological subtype, biphasic and monophasic. It has SYT-SSX gene fusion that decreases expression of p53 tumor suppressor. The prognosis is associated with mitosis and tumor diameter. Therefore this study conducted to know the pattern of p53 expresion and its association with mitosis, histological subtype, and other prognosis factors. Methods: Twenty synovial sarcoma cases consisted of 4 monophasic and 16 biphasic cases from Cipto Mangunkusumo Hospital – Faculty of Medicine, Universitas Indonesia (CMHospital-FMUI) 2005-2011 were analyzed for association of p53 expression and mitosis as prognostic factor. Haematoxylin-eosin slides were used to count mitosis. Paraffin block materials were used to analyze p53 expression by immunohistochemistry and to detect SYT gene translocation by FISH (Fluorescein in situ Hybridization). Results: The Fisher’s exact test showed that positive p53 expression was associated with tumor diameter <5 cm although it was not associated with mitosis. The histological subtype has no association with p53 expression and mitosis. Unfortunately, only 7/19 cases were positive for FISH-SYT gene translocation. Conclusion: In synovial sarcoma, p53 expression is associated with tumor diameter. (Med J Indones. 2012;21:196-202) Keywords: Mitosis, p53, synovial sarcoma, SYT-SSX fusion gene

Prognostic significance of different immunohistochemical S100A2 protein expression patterns in patients with operable nonsmall cell lung carcinoma

S100 proteins are involved in carcinogenesis, metastasis, and survival. S100A2 is a member of the S100 family, and its expression and precise role in patients with non-small cell lung carcinoma (NSCLC) has been debated. Therefore, we examined the immunohistochemical expression patterns of S100A2 in NSCLC in relation to clinicopathological parameters, important molecular biomarkers, and patient outcome. Microarray data for 74 paraffin-embedded specimens from patients with NSCLC were immunostained for S100A2 and p53 proteins. Immunohistochemical staining patterns of S100A2 in the NSCLC tissue samples examined were either nuclear (nS100A2), cytoplasmic (cS100A2), or both. A significant association between nS100A2 positivity and better disease-free interval was observed (hazards ratio 0.47; 95% confidence interval 0.23–0.99; P = 0.047). Similarly, cS100A2 negativity was marginally associated with shorter overall survival (P = 0.07). Patients without lymphatic infiltration and an earlier disease stage had significantly better overall survival and disease-free interval. The S100A2 expression pattern in operable NSCLC varies widely, and this differential expression (nuclear, cytoplasmic or both) seems to correlate with prognosis. Intensity of expression was highest in the early and advanced stages, and equally distributed in the middle stages. This observation may be indicative of a dual role for this protein both during earlier and advanced disease stages, and may also explain the differential immunoexpression of S100A2. Analysis of the disease-free interval showed that nS100A2-negative and p53-positive expression was associated with a statistically significant (P = 0.003) shorter disease-free interval in comparison with nS100A2-positive and p53-negative expression (12 versus 30 months, respectively). Further studies are required to establish whether S100A2 protein may have a substantial role as a prognostic or predictive indicator in this unfavorable group of patients.

Loss of S100A14 Expression Is Associated with the Progression of Adenocarcinomas of the Small Intestine

Objectives: Small intestinal adenocarcinoma (SIAC) is an exceedingly rare human malignant tumor, and its association with the S100A14 gene is not known yet. We aimed to investigate the clinicopathological correlations between S100A14 expression and SIAC. Methods: Immunohistochemical analyses of S100A14, p21 and p53 were performed using tissue microarray analysis of 175 surgically resected SIACs. Results: Of 175 SIACs, loss of S100A14 expression was observed in 128 cases (73.1%). Loss of S100A14 expression was associated with lymph node metastasis (p = 0.009) and advanced disease stage (p = 0.013), and was more frequently observed in distal than duodenal tumors (p = 0.043). The majority of SIACs lost p21 expression (93.7%), and significant loss of p21 expression was observed in cancers with high pT stages (pT₃ and pT₄; p = 0.011), lymph node metastasis (p = 0.029) and advanced cancer stage defined by the American Joint Committee on Cancer (p = 0.005). Overexpression of p53 was found in 23.4% of cases. Positive expression of p53 was associated with distally located SIACs (jejunum or ileum; p = 0.006). There was no association between the expression of S100A14 and p21 or p53. Conclusion: Loss of S100A14 in SIAC is common and is associated with higher metastatic potential and advanced clinical stage.

979P - Predictive and Prognostic Role of Survivin and P53 Expression in Patients with Advanced Ovarian Cancer Treated with Neoadjuvant Chemotherapy

ABSTRACT Background Qualification of patients with advanced ovarian cancer (AOC) to treatment with primary or interval debulking surgery (IDS) is the subject of controversy. The aim of this study was to assess the expressions of selected proteins of apoptosis to the effects of neoadjuvant chemotherapy (NAC) in patients with AOC. Material and methods We evaluated 60 consecutive patients with AOS (FIGO stage IIIC-IV) treated with NAC, retrospectively. Formalin-fixed, paraffin-embedded tissue specimens were immunohistochemically stained for expression of p53 and survivin in patients given platinum-based NAC undergoing IDS. The expression of survivin was adopted dichotomization by the median expression of the protein found total score (TS) equals 2. For low expression of survivin was TS ≤ 2, while high total score TS> 2 The positive and negative expression of p53 were used to dichotomization study group. Results Median age of 60 patients was 60 years. The optimal IDS was achieved in 69.1% (38/55). We observed significant difference in the percentage of stained nuclei (PS, p = 0.0002), the intensity of staining (IS, p = 0.0003) and TS (p = 0.0001) by comparing the expression of survivin in tumor tissue taken before and after NAC. The expression of p53 in tumor tissue before and after NAC was observed and significant difference was in PS, (p = 0.0424). There were no statistically significant difference in IS and the TS. Expression of survivin and p53 was not related to the results of IDS. Survivin expression was a prognostic factor in AOC patients treated with NAC (p = 0.0484). Expression of survivin and p53 proteins was not a predictor factor in AOC patients. Adverse factors affecting the PFS for AOC patients treated with NAC were: lack of optimal IDS and the lack of an objective response by RECIST criteria (respectively HR was 3.93 (95% CI, 2.07-7.46, p Conclusions High expression of survivin is a useful prognostic factor in patients treated with neoadjuvant chemotherapy for advanced ovarian cancer. This effect is more significant in patients with positive expression of p53. Disclosure All authors have declared no conflicts of interest.

An Alternative Pathway in Colorectal Carcinogenesis Based on the Mismatch Repair System and p53 Expression in Korean Patients with Sporadic Colorectal Cancer

Microsatellite instability (MSI) and chromosomal instability are main mechanisms underlying colorectal carcinogenesis. We determined the features and prognosis of colorectal cancer based on MSI including mismatch repair genes and expression of p53. Between 1999 and 2008, a total of 2,649 colorectal cancer patients were analyzed using a prospective database. A mismatch repair defect (MMR-D) was defined as a loss of expression of more than one MMR protein and/or MSI-high. MMR-proficiency (MMR-P) was defined as expression of all MMR proteins and microsatellite stable (MSS)/MSI-low. Groups 1 (G1), 2 (G2), 3 (G3), and 4 (G4) were defined as MMR-D and p53-positive expression, MMR-D and p53-negative expression, MMR-P and p53-positive expression, MMR-P and p53-negative expression, respectively. Eighty-two (3.0%), 181 (6.8%), 1,368 (51.7%), and 1,018 (38.5%) patients were classified into groups 1-4, respectively. Comparison between G1 and G2 showed differences in location (p < 0.001), size (p = 0.030), node metastasis (p = 0.027), distant metastasis (p = 0.009), and stage (p = 0.040). Comparison between G3 and G4 showed differences in location (p < 0.001) and histology (p < 0.001). Comparison between G1 and G3 showed differences in location (p < 0.001) and histology (p < 0.001). Comparison between G2 and G4 showed differences in age (p < 0.001), location (p < 0.001), size (p = 0.006), histology (p < 0.001), node metastasis (p < 0.001), distant metastasis (p < 0.001), and stage (p < 0.001). On multivariate analysis, stage (p = 0.007) and histology (p < 0.001) were associated with improved overall survival, and stage (p < 0.001) was associated with disease-free survival. According to the MSI and p53 subsets, colorectal cancers showed different clinicopathologic features, but these subsets had no prognostic impact on overall and disease-free survival rate.

Immunohistochemical study of PUMA, c-Myb and p53 expression in the benign and malignant lesions of gallbladder and their clinicopathological significances

Gallbladder cancers have a very poor prognosis without specific molecular marker being identified. In this study we studied PUMA, c-Myb and p53 expression in benign and malignant lesions of gallbladder and analyzed their clinicopathological significance. Immunohistochemical staining of PUMA, c-Myb and p53 protein was performed in 108 gallbladder adenocarcinomas, 46 peritumoral tissues, 15 polyps, and 35 chronic cholecystitis. We demonstrated that the percent of positive PUMA, c-Myb and p53 expression was significantly higher in gallbladder adenocarcinomas than in peritumoral tissues, polyps and chronic cholecystitis (p < 0.05 or 0.01). Benign gallbladder epithelium with positive PUMA, c-Myb or p53 expression showed moderately or severely atypical hyperplasia. The percent of positive PUMA, c-Myb and p53 expression was significantly higher in the cases having poorly differentiated adenocarcinoma with large tumor mass, lymph node metastasis and high invasiveness than cases with well-differentiated adenocarcinoma with small tumor mass and without metastasis and invasiveness (p < 0.05 or p < 0.01). The percent of positive PUMA, c-Myb and p53 expression was significantly higher in cases with radical resection than without resection (p < 0.05). Univariate Kaplan-Meier analysis showed that PUMA, c-Myb and p53 expression was associated with decreased overall survival (p < 0.05 or p < 0.01). Multivariate Cox regression analysis showed that PUMA, c-Myb or p53 expression was a poor-prognostic predictor in gallbladder adenocarcinoma. PUMA, c-Myb and p53 expression closely relates to the carcinogenesis, fast-progression, easy-metastasis, high-invasion, and poor-prognosis in gallbladder adenocarcinoma.

Immunohistochemical assessment of apoptosis-associated proteins: p53, Bcl-xL, Bax and Bak in gastric cancer cells in correlation with clinical and pathomorphological factors

The p53 protein as well as Bcl-2 family proteins such as Bax, Bak and Bcl-xL regulate apoptosis. The study objective was to analyze the expression of p53, Bak, Bcl-xL and Bax in gastric cancer and in healthy gastric mucosa. The study group consisted of 66 patients with gastric cancer, treated surgically in II Department of General and Gastroenterological Surgery, Medical University of Bialystok. The expression of the studied proteins was assessed using the immunohistochemical method. Significant differences were found in the expressions of the studied proteins as compared to healthy gastric mucosa. The expressions of p53 and Bax were significantly higher (70% vs 13% and 50% vs 13%), whereas those of Bak and Bcl-xL significantly lower (18% vs 83% and 74% vs 97%) in cancer cells than in normal mucosa (p<0.001). Significant differences were also noted in the expressions of Bax and Bcl-xL in relation to histological type. In the intestinal type (Lauren I), the expressions of Bax and Bcl-xL were higher as compared to the diffuse type (Lauren II) (93% vs 43% and 91% vs 43%). Simultaneously, correlations were noted between changes in the expression of Bax vs Bcl-xL and Bak. High expression of Bax showed a positive correlation with reduced Bak and Bcl-xL (p<0.05). Moreover, positive expression of p53 caused poorer distant survival of patients (p<0.05). Our study concluded that disturbances in the expression of p53, Bax, Bcl-xL and Bak proteins are associated with their involvement in the process of carcinogenesis in the stomach. It is suggesting that they might appeared in the early phase of carcinogenesis.

Biological markers of cisplatin resistance in advanced testicular germ cell tumours

Germ cell tumours (GCTs) of the testis show exquisite sensitivity to treatment with cisplatin. Despite the high cure rates provided by platinum-based chemotherapy, 10-20% of patients die from progressive disease. Although various cellular pathways may influence cisplatin efficacy, their actual impact has not been comprehensively investigated in advanced GCTs. The objective of the present study was to clarify the role of the expression status of proteins involved in the Rb and p53 tumour suppressor pathways in sensitivity and resistance of GCTs to cisplatin-based chemotherapy. Paraffin-embedded tumour tissues from 84 patients with advanced GCT treated with cisplatin-based chemotherapy were analysed. Immunohistochemical expression of proteins p53 and mdm2, and the G1-phase cyclins D1 and D2 (CD1 and CD2) was assessed and correlated with the clinical course. The percentages of positive expression of p53, mdm2, CD1 and CD2 were 56, 57, 37.5 and 55%, respectively. From univariate analysis, there was no significant association between p53, mdm2 or CD1 expression and outcome. Instead, positive CD2 expression was found to be marginally associated with shorter median duration of progression-free survival (PFS) (p=0.06). In multivariate analysis, none of the molecular markers retained statistical significance with treatment response or survival. Tissular expression of p53, mdm2 and CD1 is not associated with prognosis or treatment response in patients with advanced GCT. Aberrant CD2 expression appears to further determine a shorter PFS. Larger and further studies are required to validate CD2 as a marker of cisplatin resistance.

Impact of MDM2 polymorphism

MDM2 was originally identified as an oncoprotein that binds to p53 and inhibits p53-mediated transactivation. Scientists have described functional single-nucleotide polymorphisms (SNP) in the MDM2 gene. They showed that the genotype of SNP 309 induces an increase in the level of MDM2 protein, which causes attenuation of the p53 pathway. In this study, we sought to investigate whether this polymorphism was related to risk of colorectal cancer and whether there were relationships between SNP 309 and protein expression or clinicopathological variables in Tunisian patients. To investigate the effect of this polymorphism in colorectal cancer pathogenesis, we genotyped 167 patients and 167 blood donors. Immunohistochemistry was performed on normal mucosa and tumor. The rates of MDM2 genotypes were 6.6% for wild-type (T/T) and 93.4% for the SNP 309 polymorphic genotype (T/G and G/G) in patients and 38.3 and 61.7% in controls, respectively. There were significant differences in the frequencies of genotypes between patients and controls (P<0.01). We did not find any relationship between genotypes and clinicopathological features of patients, except in the case of the nonmucinous histological subtype (P=0.001). Moreover, we found that patients with the wild-type genotype (T/T) had significantly more favorable clinical outcome than did patients with the SNP 309 genotype (T/G, G/G) (P=0.005). In addition, we found an association between positive expression of p53 and polymorphic genotypes of MDM2 (T/G, G/G) (P=0.037). There was a significant association between tumoral immunostaning and MDM2 polymorphism (P=0.01). Our results suggest that the MDM2 polymorphism is significantly associated with colorectal cancer risk and may provide useful prognostic information for Tunisian patients with colorectal cancer.

Enhancement Patterns and Parameters of Breast Cancers at Contrast-enhanced US: Correlation with Prognostic Factors

To investigate the correlation between enhancement patterns and parameters of contrast material-enhanced ultrasonography (US) with prognostic factors in breast cancers. The study was approved by the institutional ethics committee, and written informed consent was obtained. Surgical resection specimens of 74 malignant breast lesions in 74 women (mean age, 55 years; age range, 32-78 years) who had undergone contrast-enhanced US were included. Different contrast enhancement patterns (enhancement degree, order, and margin; internal homogeneity; perfusion defect; and radial or penetrating vessels) and parameters (wash-in time, peak intensity, time to peak, area under the time-intensity curve, ascending slope, and descending slope) were evaluated. Pathologic prognostic factors, including histologic grade, lymph node status, tumor diameter, microvessel density (MVD), estrogen and progesterone receptor status, and c-erb-B2, p53, and Ki-67 expression were determined. Correlation of enhancement patterns and parameters with prognostic factors was analyzed with the Pearson χ2 test, Spearman rank correlation test, and logistic regression analysis. Some enhancement features were associated, albeit not significantly, with prognostic factors. Perfusion defect was the most accurate enhancement criterion for higher histologic grade (grade III) (P=.016), negative estrogen receptor expression (P=.006), positive c-erb-B2 expression (P=.013), larger tumor diameter (≥2 cm) (P=.016), and increased MVD (P=.019). Radial or penetrating vessels were associated with lymph node status (P=.010). Hyperenhancement may be useful in reflecting increased MVD (P=.008) and positive p53 expression (P=.037). For contrast enhancement parameters, ascending slope was the best discrimination criterion for proliferative activity (P=.003). Enhancement patterns and parameters of contrast-enhanced US may be useful in the noninvasive prediction of prognostic factors of breast cancers.

The Prognostic Significance of Apoptosis-Related Biological Markers in Chinese Gastric Cancer Patients

Background and Objective The prognosis varied among the patients with the same stage, therefore there was a need for new prognostic and predictive factors. The aim of this study was to evaluate the relationship of apoptosis-related biological markers such as p53, bcl-2, bax, and c-myc, and clinicopathological features and their prognostic value.MethodsFrom 1996 to 2007, 4426 patients had undergone curative D2 gastrectomy for gastric cancer at Fudan University Shanghai Cancer Center. Among 501 patients, the expression levels of p53, bcl-2, bax, and c-myc were examined by immunohistochemistry. The prognostic value of biological markers and the correlation between biological markers and other clinicopathological factors were investigated.ResultsThere were 339 males and 162 females with a mean age of 57. The percentages of positive expression of p53, bcl-2, bax, and c-myc were 65%, 22%, 43%, and 58%, respectively. There was a strong correlation between p53, bax, and c-myc expression (P = 0.00). There was significant association between bcl-2, and bax expression (P<0.05). p53 expression correlated with histological grade (P = 0.01); bcl-2 expression with pathological stage (P = 0.00); bax expression with male (P = 0.02), histological grade (P = 0.01), Borrmann type (P = 0.01), tumor location (P = 0.00), lymph node metastasis (P = 0.03), and pathological stage (P = 0.03); c-myc expression with Borrmann type (P = 0.00). bcl-2 expression was related with good survival in univariate analysis (P = 0.01). Multivariate analysis showed that bcl-2 expression and pathological stage were defined as independent prognostic factors. There were significant differences of overall 5-year survival rates according to bcl-2 expression or not in stage IIB (P = 0.03).ConclusionThe expression of bcl-2 was an independent prognostic factor for patients with gastric cancer; it might be a candidate for the gastric cancer staging system.

Correlations of Hormone Receptors (ER and PR), Her2/neu and p53 Expression in Breast Ductal Carcinoma Among Yemeni Women

Aims: The purpose of this study was to determine if any relationship exists between Estrogen Receptor (ER),Progesterone Receptor (PR), Her2/neu, P53, and clinicopathological factors in female breast ductal carcinoma. Materials and Methods: One hundred and thirty seven (IDC=124, NIDC=13) ductal carcinomas were clinicopathologically and immunohistochemically analyzed and compared with 20 control cases of benign breast lesions in which assessment of Her-2/neu, ER, PR, and P53 has been performed, prospectively. Chi-square analysis was then used to correlate the above observations. Results: The overall immunoexpression of ER, PR, Her2/neu and P53 were 43.8%, 27%, 30.6% and 48.9%, respectively, of the 137 ductal carcinomas. A significant Positive association between ER or PR expression with lymph node involvement was found ( p= 0.004, p= 0.022 respectively), while p53 was found to be negatively associated with lymph nodes involvement (p= 0.03, 0.02, respectively). P53 also associated negatively to lymph node status (P=0.03) and positively with borderline tumor grade (p= 0.03). Conclusion: There are high rates of positive expression of ER, PR, Her2/neu and P53 among Yamani women with breast ductal carcinoma.

P4-09-11: Kinesin Family Member 2C (KIF2C) Is a New Surrogate Prognostic Marker in Breast Cancer (BC).

Abstract Introduction Gene expression microarrays, artificial neural network (ANN), tissue microarray and immunohistochemistry (IHC) techniques allow for the analysis of huge numbers of gene transcripts and their corresponding proteins and have been widely applied in predicting clinical outcome. Methods 1- In this study, we analysed 48,000 gene transcripts of 171 unselected series of BC using ANN and pathways analysis to identify genes that can be used to predict clinical outcome of BC. 2- The clinic-pathological outcome of candidate genes were validated by using IHC in 4 independent primary BC data sets: a) a series of 379 consecutive high risk BC (NPI&amp;gt;3.4) who treated with surgery (S)+ radiotherapy (RT) and did not received neither endocrine (ET) nor chemo-therapies (CT), b) A series of 1650 consecutive cases of BC who treated with S + RT and received adjuvant CMF and/or ET according to Nottingham prognostic index (NPI), menopausal and ER status, c) 250 locally advanced BC treated with anthracycline-based combination with or without Taxane followed by S + RT and d) 145 BC overexpressing HER-2 treated with S + RT followed by sequential adjuvant anthracycline combination CT + trastuzumab. Results Gene expression analysis ANN analysis revealed that KIF2C gene was the highest ranked gene that predicted clinical outcome and accurately differentiated between low and high grade BC based on a 10-fold external cross-validation analysis with an average classification accuracy of &amp;gt;98%. High KIF2C gene expression level was associated with shortest BC specific survival (BCSS), disease free (DFS) and distal metastasis free survivals (DM-FS); p&amp;lt;0.0001. In univariate analysis, high level of KIF2C gene expression was associated with large tumour size, higher lymph node stage, negative ER, positive p53 expression and HER2 overexpression. However in multivariate analysis, KIF2C gene expression level was only statistically associated with histological grade (p&amp;lt;00001) and mitosis (p&amp;lt;0.0001). Pathways analysis revealed that KIF2C is likely to play a significant role in cytokinesis, cell division and cell cycle regulations. Immunohistochemistry 75% of BC showed overexpression of KIF2C protein. KIF2C protein overexpression was associated with unfavourable clinic-pathological features including high grade, high mitotic index, basal like phenotype, triple negative phenotype, HER2 overexpression, TOP2A overexpression, p53 mutation, and loss of BRCA1 (adjusted p&amp;lt;0.0001). In univariate analysis, KIF2C protein overexpression was associated with patient's BCSS in both ER+/high risk patients (NPI &amp;gt; 3.4) who did not received ET (HR: 3.3, 95% CI: 1.2−9.3, p=0.02) and ER-/high risk patients who did not received CT (HR: 3.2, 95% CI: 1.1−8.8, p=0.025). In 1650 BC series, multivariate Cox regression model including validated prognostic factors, confirmed that KIF2C overexpression is an independent prognostic factor. KIF2C overexpression showed increase in the risk of death (HR: 1.5, 95% CI: 1.1−2.0, p=0.009), recurrence (HR: 1.4, 95% CI: 1.1−1.8, p=0.017) and DM (HR: 1.6, 95% CI: 1.2−2.3, p=0.005). In conclusion, our findings provide a new insight to a better understanding of mammary carcinogenesis and that KIF2C is a promising molecular prognostic factor and a potential therapeutic target. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-11.

Early evaluation of the apoptotic index ratio is useful in predicting the efficacy of chemoradiotherapy in esophageal squamous cell carcinoma

Chemoradiotherapy for advanced esophageal cancer is a standard treatment alongside surgical treatment. Although numerous investigators have attempted to identify the predictive markers for chemoradiosensitivity, there appear to be few candidates that can be applied in clinical use. Using biopsy specimens, we investigated the apoptotic index (AI) prior to treatment and following a radiation dose of 10 Gy to detect the early response to chemoradiotherapy in 28 patients with esophageal squamous cell carcinoma. Molecular markers, including p53, p21, bax, bcl-2, HSP27, HSP70, HSP90, Ku70, Ku86 and HIF-1α, were also examined by immunohistochemical staining. The patients were divided into two groups depending on the response to chemoradiotherapy: a responder group (RG) (n=19) that included the patients with complete or partial response, and a non-responder group (NRG) (n=9), that included patients with stable or progressive disease. In the RG and NRG, the AI of pretreatment was 4.7±5.3 (mean ± SD, cells/1,000 cells) and 5.9±3.7, respectively. The apoptotic index ratio (AIR), which was determined by dividing the AI following 10 Gy radiation by the pretreatment AI, was higher in the RG compared to the NRG (4.7±4.5 versus 1.9±1.4, p=0.03). When the cut-off value of AIR was set at 2.4, the sensitivity, specificity and accuracy were 74, 78 and 76%, respectively. Among the molecular markers we examined immunohistochemically, a positive p53 expression in the pretreatment evaluation was associated with the efficacy of chemoradiotherapy (p=0.08). Regarding the expression of other molecular markers, no significant correlations were found in RG and NRG. In the present study, the results indicated that AIR is useful for the prediction of chemoradiosensitivity in esophageal squamous cell carcinoma.

P53 expression in liver tissue of patients with chronic hepatitis B and its influencing factors

To observe p53 expression in liver tissue of patients with chronic hepatitis B and its influencing factors. 17 cases HBeAg-negative chronic hepatitis B patients and 31 cases HBeAg-positive chronic hepatitis B patients were divided into 2 groups. (1) HBeAg-negative chronic hepatitis B patients were older, mostly male and HBV DNA lower. These three indicators between two groups patients appeared statistical difference. Serum markers were no statistical difference between two groups patients except Glo. (2) Pathological inflammation and fibrosis Staging were no statistical difference between two groups patients. p53 expression positive rate and p53 expression semi-quantitative scoring in liver tissue were no statistical difference between the two groups. (3) Logistic regression analysis showed that only liver fibrosis staging (S) is a risk factor for p53 expression. Compared with the S0-1, p53 expression increased by 3.9 times the rate of positive in S > or = 2. Liver fibrosis staging in patients with chronic hepatitis B is a risk factor for p53 positive expression in liver.

Mitochondrial UCP4 and bcl-2 expression in imprints of breast carcinomas: Relationship with DNA ploidy and classical prognostic factors

Mitochondria are the bioenergetic and metabolic centers of cells and play an important role in the regulation of cell death. The mitochondrial apoptosis pathway is controlled by the bcl-2 protein family. Overexpression of mitochondrial uncoupling protein 4 (UCP4) can promote proliferation and inhibit apoptosis and differentiation. Imprint smears obtained from 124 tumors were studied immunocytochemically, and results were correlated with prognostic markers. There were 112 ductal and 12 lobular carcinomas. The positivity of UCP4 was correlated with lymph node metastases ( p = 0.005), positive ER and PR expression ( p < 0.0001 for both), as well as positivity for p53 ( p < 0.0001) and Ki-67 ( p < 0.0001). Decreased expression of bcl-2 correlated with increased expression of UCP4 ( p = 0.001). Regarding DNA ploidy, UCP4 positivity was correlated with aneuploid tumors ( p = 0.002). Negative expression of bcl-2 was correlated with poorly differentiated carcinomas ( p < 0.0001), as well as with positive expression of p53 ( p < 0.0001) and Ki-67 ( p < 0.0001). Logistic regression revealed that ploidy and p53 expression had an impact on UCP4. These findings encourage future investigations regarding the potential role of UCPs not only into mechanisms underlying breast cancer, but also as a novel candidate to the design and development of more effective therapeutic strategies.

HER-2 Positive and p53 Negative Breast Cancers are Associated With Poor Prognosis

p53 and HER-2 coexpression in breast cancer has been controversial. These markers were tested using immunohistochemistry and HercepTest. HER-2 expression is related to reduced breast cancer survival (p = .02) . p53 expression relates to HER-2 expression (p = .029). Coexpression between p53 and HER-2 has no relation to prognosis. On univariate and multivariate analysis, combination of HER-2 positive and p53 negative expression was associated with a poor prognosis (p = .018 and p = .027, respectively), while the combination of HER-2 negative and p53 positive expression was associated with a favorable prognosis (p = .022 and p = .010, respectively). Therefore the expression of these markers should be considered collectively.

Placental Alkaline Phosphatase in Pediatric Adrenocortical Cancer

The germline R337H mutation in the TP53 gene is considered to be responsible for the increased incidence of adrenocortical tumors (ACTs) in children from Brazil. High level production of hormones in ACTs (>95%) cause virilization alone (60%), Cushing syndrome (<5%), the mixed type (30%), or other rarer manifestations. ACT probably develops owing to events occurring during the final stages of intrauterine life based on the very common early onset of signs and symptoms shortly after birth. In this study, we determined by immunohistochemistry and enzyme assays whether placental alkaline phosphatase (PLAP) is expressed in pediatric ACTs. Immunohistochemical analysis revealed positive p53 expression in 88% of the tested ACTs (29 of 33). PLAP was detected at a slightly lower frequency based on immunohistochemical (17 of 33, 51%) and enzyme activity analyses (9 of 16, 56%). In conclusion, probably at a certain time point during adrenocortical development (end of gestation to early postnatal period), some fetal zone cells survive owing to defective apoptosis and develop into childhood ACT, maintaining some characteristics of the embryonal period, such as PLAP expression. Further studies of PLAP should investigate the functional role, if any, of PLAP in such tumors.