Negative P53 Expression Research Articles

Factors affecting platinum sensitivity in cervical cancer.

The present study aimed to investigate the association between nedaplatin (NDP) sensitivity and the expression of biological factors in cervical cancer. A total of 45 cervical cancer specimens, including 18 pretreatment biopsies and 27 surgical specimens, were used in histoculture drug response assays to determine the chemosensitivity of cervical cancer specimens to NDP. Each specimen was assessed for immunohistochemical expression of Ki-67, p53, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), cleaved caspase-3, cyclooxygenase-2 (COX-2), and excision repair cross-complementation group 1 (ERCC1). The results revealed that low or negative expression of p53, Bcl-2 and COX-2, and high or positive expression of cleaved caspase-3 were significantly correlated with high sensitivity to NDP. However, there were no significant differences in Ki-67, Bax or ERCC1 expression between the low and high sensitivity groups. These findings indicate that sensitivity to platinum may be easily predicted by immunostaining for the detection of these specific factors in pretreatment biopsies or surgical specimens. The expression profiles of these targets may therefore provide additional information for planning individualized chemotherapy in the treatment of cervical cancer.

Comparative analysis of p53 and p21 proteins in normal cervix and HPV associated precancerous and cancerous lesions of cervix

IntroductionHPV-E6 oncoprotein of High-Risk HPV plays critical role in the degradation of p53 protein for acquisition of malignant phenotype in cervix cells. The present study, was sought to analyze the expression of HPV-E6, p53 and p21 in cervical cancer to explore possible impact of HPV-E6 in the modulation of these proteins. MethodsThe expression of HPV16/18-E6, p53 and p21 proteins in cervix tissues [normal (n = 100), cervical intraepithelial neoplasia (CIN; n = 67), squamous cell carcinoma (SCCs; n = 153)] was analyzed by immunohistochemistry and revalidated by Western Blotting. The p53 protein functionality was determined by using phosphospecific p-p53-ser46 antibody. ResultsThe negative expression of HPV-E6 and p53 but, mild immunoreactivity of p21 was noticed in normal stratified squamous epithelium. In CIN and SCCs, the HPV-E6 was found to be predominantly over-expressed in 80.0% and 84.9% of cases respectively. Significant nuclear accumulation of p53 was observed in 77.6% of precancerous and 83.0% of cancerous tissues whereas, 74.6% of CIN and 73.8% of SCCs represented loss of nuclear p21 expression as compared to normal (p = 0.0001, p = 0.0001). Pearson's correlation test revealed significant inverse association between p53 and p21 proteins both in CIN (p = 0.0001) and SCCs (p = 0.0001). Interestingly, significant positive association of HPV-E6 with p53 and negative association with p21 were also detected in CIN (p = 0.0001) and SCCs (p = 0.0001). No positive expression of p-p53-ser46 was detected in any of the cases. DiscussionThe present study provides the evidences of inhibition of p53 and p21 transactivity by HPV-E6 resulting alteration of cell growth inhibitory signals in cervical cancer.

Loss of Tumor Suppressor ARID1A Protein Expression Correlates with Poor Prognosis in Patients with Primary Breast Cancer.

PurposeSomatic mutations of the chromatin remodeling AT-rich interactive domain 1A (SWI-like) gene (ARID1A) have been identified in many human cancers, including breast cancer. The purpose of this study was to evaluate the nuclear expression of ARID1A in breast cancers by immunohistochemistry (IHC) and to correlate the findings to clinicopathologic variables including prognostic significance.MethodsIHC was performed on tissue microarrays of 476 cases of breast cancer. Associations between ARID1A expression and clinicopathologic characteristics and molecular subtype were retrospectively analyzed.ResultsLow expression of ARID1A was found in 339 of 476 (71.2%) cases. Low expression of ARID1A significantly correlated with positive lymph node metastasis (p=0.027), advanced pathologic stage (p=0.001), low Ki-67 labeling index (p=0.003), and negative p53 expression (p=0.017). The ARID1A low expression group had significantly shorter disease-free and overall survival than the ARID1A high expression group (p<0.001 and p<0.001, respectively). Multivariate analysis demonstrated that low expression of ARID1A was a significant independent predictive factor for poor disease-free and overall survival in patients with breast cancer (disease-free survival: hazard ratio, 0.38, 95% confidence interval [CI], 0.20-0.73, p=0.004; overall survival: hazard ratio, 0.11, 95% CI, 0.03-0.46, p=0.003). In patients with luminal A type disease, patients with low ARID1A expression had significantly shorter disease-free and overall survival rates than patients with high ARID1A expression (p=0.022 and p=0.018, respectively).ConclusionLow expression of ARID1A is an independent prognostic factor for disease-free and overall survival in breast cancer patients and may be associated with luminal A type disease. Although the biologic function of ARID1A in breast cancer remains unknown, low expression of ARID1A can provide valuable prognostic information.

P53-dependent activation of microRNA-34a in response to etoposide-induced DNA damage in osteosarcoma cell lines not impaired by dominant negative p53 expression.

Osteosarcoma (OS) is the most common primary malignant bone tumor and prevalently occurs in the second decade of life. Etoposide, a chemotherapeutic agent used in combined treatments of recurrent human OS, belongs to the topoisomerase inhibitor family and causes DNA breakage. In this study we evaluated the cascade of events determined by etoposide-induced DNA damage in OS cell lines with different p53 status focusing on methylation status and expression of miR-34a that modulate tumor cell growth and cell cycle progression. Wild-type p53 U2-OS cells and U2-OS cells expressing dominant-negative form of p53 (U2- OS175) were more sensitive to etoposide than p53-deficient MG63 and Saos-2 cells, showing increased levels of unmethylated miR-34a, reduced expression of CDK4 and cell cycle arrest in G1 phase. In contrast, MG63 and Saos-2 cell lines presented aberrant methylation of miR-34a promoter gene with no miR-34a induction after etoposide treatment, underlining the close connection between p53 expression and miR-34a methylation status. Consistently, in p53siRNA transfected U2-OS cells we observed loss of miR-34a induction after etoposide exposure associated with a partial gain of gene methylation and cell cycle progress towards G2/M phase. Our results suggest that the open and unmethylated conformation of the miR-34a gene may be regulated by p53 able to bind the gene promoter. In conclusion, cell response to etoposide-induced DNA damage was not compromised in cells with dominant-negative p53 expression.

MiR-34a-5p suppresses colorectal cancer metastasis and predicts recurrence in patients with stage II/III colorectal cancer.

Although surgery remains the mainstay of curative treatment for colorectal cancer (CRC), many patients still have high chance to experience disease relapse. It is therefore imperative to identify prognostic markers that can help predict the clinical outcomes of CRC. Aberrant microRNA expression holds great potential as diagnostic and prognostic biomarker for CRC. Here we aimed to investigate clinical potential of miR-34a-5p as a prognostic marker for CRC recurrence and its functional significance. First, we validated that miR-34a-5p was downregulated in CRC tumour tissues (P<0.05). The expression level of tissue miR-34a-5p was then evaluated in two independent cohorts of 268 CRC patients. miR-34a-5p expression was positively correlated with disease-free survival in two independent cohorts (cohort I: n=205, P<0.001; cohort II: n=63, P=0.006). Moreover, the expression of miR-34a-5p was an independent prognostic factor for CRC recurrence by multivariate analysis (P<0.001 for cohort I, P=0.007 for cohort II). Ectopic expression of miR-34a-5p in p53 wild-type colon cancer cell HCT116 significantly inhibited cell growth, migration, invasion and metastasis. miR-34a-5p induced cell apoptosis, cell cycle arrest at G1 phase and p53 transcription activity in HCT116 cells, but not in the HCT116 p53 knockout (p53(-/-)) cells. miR-34a-5p significantly suppressed the HCT116 growth in vivo, whereas it showed no effect on the HCT116 p53(-/-) xenograft, indicating that the growth-inhibiting effect by miR-34a-5p was dependent on p53. In addition, the expression level of miR-34a-5p in patients with p53-positive expression was higher than that in patients with p53-negative expression (P<0.01). In conclusion, miR-34a-5p inhibits recurrence of CRC through inhibiting cell growth, migration and invasion, inducing cell apoptosis and cell cycle arrest in a p53-dependent manner.

P53 is an independent prognostic factor in operable esophageal squamous cell carcinoma: a large-scale study with a long follow-up.

The p53 protein is involved in many biological functions in cancer, such as cell cycle arrest, DNA repair, apoptosis, senescence, DNA metabolism, angiogenesis, and cellular differentiation. However, the association between p53 expression and clinicopathological findings or prognosis in esophageal squamous cell carcinoma (ESCC) is controversial. We designed a large-scale study of 830 operable ESCC patients with a long follow-up to investigate the relationship between p53 expression and the clinicopathological characteristics and prognosis of patients. Immunohistochemistry was used to detect p53 protein expression. When the patients were divided into two groups, a positive expression group and a negative expression group, p53-positive expression positively correlated with a poorer differentiation level (P = 0.044). The overexpression of p53 was associated with a more advanced clinical stage (P = 0.015). A total of 775 patients were available for survival analysis. The median OS of 160 patients who had p53-positive expression and 486 patients who had p53-negative expression were 58.8 and 46.3 months, respectively (P = 0.021); the median PFS of the two groups were 39.6 and 27.5 months, respectively (P = 0.015). Lymph node metastasis, gender, differentiation, depth of invasion, and p53 protein expression were proven to have an influence on both OS and PFS in a univariate analysis. In the multivariate analysis, p53-positive expression maintained its independent prognostic impact on OS (P = 0.048) and PFS (P = 0.039), as did lymph node metastasis, differentiation, and depth of invasion. We identified that p53 protein-positive expression can serve as an independent, unfavorable prognosis biomarker in ESCC.

Human papillomavirus infection in Bowen disease: negative p53 expression, not p16(INK4a) overexpression, is correlated with human papillomavirus-associated Bowen disease.

Genital Bowen disease (BD) has been linked to the high-risk types of human papillomavirus (HPV) infection. Recently, it has been recognized that HPV also can be associated with extragenital BD. HPV oncoproteins E6 and E7 interfere with the function of p53 and pRb, respectively, leading carcinogenesis. p16(INK4a) overexpression induced by inactivation of pRb is recognized as a surrogate marker for HPV-associated cervical cancer. In this study, we examined the presence of HPV DNA in 142 BD lesions by polymerase chain reaction (PCR), and determined the type of HPV by PCR restriction fragment length polymorphism or direct DNA sequencing. HPV DNA was detected in 66.7% of genital BD and 8.3% of extragenital BD. The types of HPV detected were HPV types 6, 16, 33, 52, 56, 58 and 59. We also investigated the expression of p16(INK4a) , pRb and p53 by immunohistochemistry. Positive expression was detected in 88.6% for p16(INK4a) , 25.2% for pRb, and 63.8% for p53. There was no significant difference in p16(INK4a) and pRb expression between HPV-positive and -negative BD. However, a strong correlation of HPV positivity with p53 negativity was found. A total of 66.7% of HPV-positive BD showed no p53 expression, whereas the corresponding rate was 32.8% of HPV-negative BD. This study demonstrated that HPV can participate in the development of BD, not only in the genital lesion, but also in extragenital lesion. p16(INK) (4a) overexpression is not a marker for HPV infection in BD. Instead, negative p53 expression is correlated with HPV-associated BD.

Survivin Expression as a Prognostic Factor in Patients With Epithelial Ovarian Cancer or Primary Peritoneal Cancer Treated With Neoadjuvant Chemotherapy

The aim of this study was to evaluate association of expression of survivin and p53 with the effects of neoadjuvant chemotherapy (NAC) in patients with advanced ovarian cancer (AOC). We retrospectively evaluated 60 consecutive patients with AOC (International Federation of Gynecology and Obstetrics stage IIIC-IV) treated with NAC. The expression of p53 and survivin was assessed immunohistochemically. The median of expression total score survivin equals 2 was adopted to dichotomize the group. The positive and negative expression of p53 was used to dichotomize the group. The expression of survivin in tumor tissue taken before and after NAC was a significant difference in the percentage of stained nuclei (P = 0.0002), the intensity of staining (P = 0.0003), and total score (P = 0.0001). There was a significant difference in p53 expression in tumor tissue before and after NAC in the percentage of stained nuclei (P = 0.0424). Survivin expression, in contrast to p53 expression, was a prognostic factor in patients with AOC treated with NAC (P = 0.0484). The expression of survivin and p53 was not a predictive factor. Independent adverse predictor factors were as follows: lack of optimal interval debulking surgery and the lack of an objective response (the respective hazard ratio was 3.93 [95% confidence interval, 2.07-7.46; P < 0.0001] and 2.36 [95% confidence interval,1.25-4.47; P = 0.0080]). The suboptimal range of interval debulking surgery, resistance to platinum, and the lack of paclitaxel in the NAC were adverse prognostic factors (the respective hazard ratio was 2.61 [95% confidence interval, 1.17-5.83], 2.72 [95% confidence interval, 1.07-6.89], and 2.56 [95% confidence interval, 1.06-6.18]; P < 0.05]). High expression of survivin could be a prognostic factor in patients treated with NAC for AOC.

Comment on Fu et al.: A systematic review of p53 as a biomarker of survival in patients with osteosarcoma

To the Editor: In this meta-analysis, Fu et al. [1] performed a systematic review to assess the effect of upregulated p53 on the 3-year overall survival and the 3-year disease-free survival by calculating the pooled odds ratio (OR) with corresponding 95 % confidence interval (95 % CI). They reached an important conclusion that patients with upregulated p53 were obviously associated with decreased 3-year overall survival (OR=0.29; 95 % CI, 0.19–0.43; P<0.001) and decreased 3-year diseasefree survival (OR=0.06; 95% CI, 0.02–0.23; P<0.001). It is a valuable study. Nevertheless, there are some comments we would like to raise related to this article. Firstly, we think there are some deficiencies in literature search. Third electronic databases (Medline, Embase, and China Biology Medicine database) were systematically searched by the investigators. The small number of required papers would be an important limitation of the review. We hope that more electronic databases can be systematically searched. Meanwhile, the investigators did not focused specifically or in any details on the issue of the completeness of the search strategy report for databases, which play an important role in systematic reviews. We suggest that the investigators provide us a complete search protocol to strengthen the credibility of the system review. Secondly, the investigators might ignore some important procedures in this system review. They did not provide us the characteristics of the eligible studies, such as case number, age, sex, p53 expression level classification, and osteosarcoma classification. Moreover, the investigators also did not make sensitivity analyses to explain the different parameters in these included studies. In addition, the investigators should also provide us the correlation of p53 with clinicopathological parameter. We are eager to know why they did not provide us this information. Thirdly, the investigators included five Chinese studies [2–6]. We read these studies carefully and think that the study by Zhang et al. [3] should be excluded from the system review. Zhang et al. reported that p53 expression did not enter the regression model and there has no significances between p53 positive expression and p53 negative expression. Finally, the investigators used the odds ratio (OR) to report the risk value rather than relative risk (RR). As there are 15 studies finally included, RR can report the real risk value fold better than OR. Therefore, we suggest that RR should be used to report the risk value in this system review. We agree that p53 is an effective biomarker of survival in patients with osteosarcoma. However, the limited sample size may inevitably increase the risk of bias or random errors. Therefore, more studies with a large sample size are needed to identify the effect of p53 expression in the osteosarcoma patients.

Biological significance of promoter hypermethylation of p14/ARF gene: Relationships to p53 mutational status in Tunisian population with colorectal carcinoma

One of the most important pathways which are frequently affected in colorectal cancer is p53/ (MDM2)/p14ARF pathway. We aim to determine the methylation pattern of p14/ARF in relation to mutation of p53. This correlation was studied to investigate whether their alterations could be considered as a predictor factor of prognosis in colorectal cancer and whether it can be useful in early-stage diagnosis. Statistical analyses show that p14/ARF hypermethylation was correlated with rectum location (p = 0.004), primary TNM stage (p = 0.016), and advanced Astler–Coller stage (p = 0.024). The RT-PCR that revel 31 % of patients did not express p14/ARF mRNA or at very low level. A high concordance between CpG hypermethylation and the low levels (p < 0.005) was shown. In addition, our analyses demonstrate that patients with mutation in the p53 gene have a lack of the protein expression (p < 0.005). This category with negative expression of p53 had a shorter survival rate (p < 0.005). On the one hand, MSP pattern of p14/ARF were correlated with a lack of p53 expression (p = 0.007). We found that p53/p14ARF pathway was frequently deregulated among our patients. In our study, we demonstrate that hypermethylation of p14/ARF occurs early during CRC tumorogenesis. However, we did not find correlation between p14/ARF and survival. These results suggest that p14/ARF methylation pattern may constitute a predictor factor of CRC in early stage but it could not be considered as a prognostic factor. On the other hand and because of the reversibility of the methylation mechanism, it may be appropriate to target the demethylation of p14/ARF to develop new drogues for CRC.

The Occasional Role of Low-risk Human Papillomaviruses 6, 11, 42, 44, and 70 in Anogenital Carcinoma Defined by Laser Capture Microdissection/PCR Methodology

Low-risk human papillomaviruses (LR-HPVs) have been associated occasionally with clinically and pathologically unusual anogenital malignancies. The relation between clinicopathologic features and any pathogenetic role of LR-HPV remains unclear. From a global study of 13,328 anogenital carcinomas, we identified 57 cases in which whole-tissue polymerase chain reaction using SPF10-LiPA25 showed single LR-HPV infection. In 43/46 (93.5%) available carcinomas, multiple polymerase chain reaction assays confirmed single detection of HPV6, 11, 42, 44, or 70 DNA. In 75% (n=32) of these, LR-HPV DNA was confirmed in tumor cells by laser capture microdissection. In 2 cases, including 1 adenocarcinoma, viral DNA was only found outside the tumor. All anogenital tumors with confirmed HPV6/11 showed a distinctive range of papillary, warty or warty-basaloid, squamous, or transitional histology with patchy or negative p16 expression. HPV6-associated cervical tumors occurred at a low median age. HPV42/70 was associated with typical squamous cell carcinoma showing diffuse p16 staining like high-risk HPV-related malignancies. HPV44 was found in malignant cells in 1 case. Viral taxonomy and theoretical analysis show that HPV6/11 belong to a different genus from HPV42/70 with E6/E7 gene products that would not bind pRb or p53, whereas HPV42/70 could bind pRb. Our data support the causal involvement of LR-HPVs in the carcinogenesis of <2% of anogenital malignancies of 2 distinct clinicopathologic patterns related to the genetic structure of the HPV types 6/11 and 70/42. HPV42/70 was associated with typical squamous carcinomas. Importantly all carcinomas associated with HPV6/11 globally showed verruco-papillary, well-differentiated, squamous, or transitional histology without p16 expression.

Clinical study of the predictors to neoadjuvant chemotherapy in patients with advanced gastric cancer

To investigate the predictive value of seven gastric cancer-associated factors on neoadjuvant chemotherapy in patients with advanced gastric cancer. Expressions of C-met, EGFR, HER2, Ki-67, MMP7, P53 and TOPOII were detected by immunohistochemistry in gastric cancer tissues of 53 cases before and after mFOLFOX7 neoadjuvant chemotherapy. Chemotherapy efficacy was evaluated according to RECIST 1.1 standard combined with histopathology, and the relationship between various genes and chemotherapy efficacy was analyzed by univariate and logistic multivariate regression analyses. The clinical response rate was 52.8% (28/53) in neoadjuvant chemotherapy, including complete response in none, partial response in 28 cases (52.8%), stable disease in 24 cases (45.3%) and progressive disease in 1 case (1.9%). The expressions of all the genes were not significantly different before and after neoadjuvant chemotherapy (P>0.05). Neoadjuvant chemotherapy efficacy was 83.3% (10/12) in the patients of HER2 positive expression and 43.9% (18/41) in the patients of HER2 negative expression. The former was significant higher than the latter (P=0.016). Response rate of patients with P53 positive expression was 35.7% (10/28), significantly lower than 72.0% (18/25) of those with P53 negative expression (P=0.008). Six patients with both HER2 positive expression and P53 negative expression showed better efficacy. The expressions of C-met, EGFR, Ki-67, MMP7 and TOPOII were not associated with response to neoadjuvant chemotherapy (P>0.05). HER2 and P53 were independent influencing factors of neoadjuvant chemotherapy (P<0.05). Expressions of HER2 and P53 have great value in the prediction of mFOLFOX7 neoadjuvant chemotherapy efficacy, suggesting that as independent factors, HER2 and P53 may be used to predict the efficacy before chemotherapy.

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.

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.

Aggressive giant cell glioblastoma with negative p53 expression: case report

AbstractGlioblastoma (GBM) is the most common intrinsic brain tumor in adults, accounting for 67% of primary brain tumors. Giant cell glioblastoma (GCG) is a rare variation of GBM, occurring in less than 5% of the cases. GCG has been demonstrated to affect younger patients and have a more indolent course than traditional GBM with longer survival rates. Age, surgical resection, and genetic features are likely related with better prognosis. The presence of a p53 mutation is found in 75% of GCG with this more indolent behavior. We present a case of a 72 years-old female who presented with an extremely aggressive GCG without p53 expression who had an unusually rapid neurological deterioration and tumor regrowth after surgical excision.

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.

The p53 breast cancer tissue biomarker in Indian women

Combination chemotherapy is highly effective in locally advanced breast cancer. A negative expression of biomarker p53 indicates a higher chance of responding to this regimen. Patients' p53 status may be used as a biological cancer marker to identify those who would benefit from more aggressive treatments. The role of p53 in modulating apoptosis has suggested that it may affect the efficacy of anticancer agents. p53 alterations in 80 patients with locally advanced breast cancer IIIB undergoing neoadjuvant chemotherapy were prospectively evaluated. Patients received three cycles of paclitaxel (175 mg/m(2)) and doxorubicin (60 mg/m(2)) every 21 days. Tumor sections were analyzed before treatment for altered patterns of p53 expression, using immunohistochemistry and DNA sequencing. An overall response rate of 83.5% was obtained, including 15.1% complete pathological responses. The regimen was well tolerated with 17.7% grade 2/3 nausea and 12.8% grade 3/4 leukopenia. There was a statistically significant correlation between response and expression of p53. Of 25 patients who obtained a complete clinical response, only two were classified as p53-positive (P = 0.004, χ(2)). Of 11 patients who obtained a complete pathological remission, one was positive (P = 0.099, χ(2)). Immunohistochemical (IHC) analysis has been shown to be a prognostic factor for patients with breast cancer in India. Paclitaxel is one of the most promising anticancer agents for the therapy of breast cancer, where it has also shown activity in tumors resistant to doxorubicin.

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.

Expression patterns of Bmi‐1 and p16 significantly correlate with overall, disease‐specific, and recurrence‐free survival in oropharyngeal squamous cell carcinoma

The objective of this study was to link expression patterns of B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and p16 to patient outcome (recurrence and survival) in a cohort of 252 patients with oral and oropharyngeal squamous cell cancer (OSCC). Expression levels of Bmi-1 and p16 in samples from 252 patients with OSCC were evaluated immunohistochemically using the tissue microarray method. Staining intensity was determined by calculating an intensity reactivity score (IRS). Staining intensity and the localization of expression within tumor cells (nuclear or cytoplasmic) were correlated with overall, disease-specific, and recurrence-free survival. The majority of cancers were localized in the oropharynx (61.1%). In univariate analysis, patients who had OSCC and strong Bmi-1 expression (IRS >10) had worse outcomes compared with patients who had low and moderate Bmi-1 expression (P = .008; hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.167-2.838); this correlation was also observed for atypical cytoplasmic Bmi-1 expression (P = .001; HR, 2.164; 95% CI, 1.389-3.371) and for negative p16 expression (P < .001; HR, 0.292; 95% CI, 0.178-0.477). The combination of both markers, as anticipated, had an even stronger correlation with overall survival (P < .001; HR, 8.485; 95% CI, 4.237-16.994). Multivariate analysis demonstrated significant results for patients with oropharyngeal cancers, but not for patients with oral cavity tumors: Tumor classification (P = .011; HR, 1.838; 95%CI, 1.146-2.947) and the combined marker expression patterns (P < .001; HR, 6.254; 95% CI, 2.869-13.635) were correlated with overall survival, disease-specific survival (tumor classification: P = .002; HR, 2.807; 95% CI, 1.477-5.334; combined markers: P = .002; HR, 5.386; 95% CI, 1.850-15.679), and the combined markers also were correlated with recurrence-free survival (P = .001; HR, 8.943; 95% CI, 2.562-31.220). Cytoplasmic Bmi-1 expression, an absence of p16 expression, and especially the combination of those 2 predictive markers were correlated negatively with disease-specific and recurrence-free survival in patients with oropharyngeal cancer. Therefore, the current results indicate that these may be applicable as predictive markers in combination with other factors to select patients for more aggressive treatment and follow-up.

Clinicopathological and patient characteristics of early gastric neoplasia endoscopically resected with loss of Mlh1 expression

Hypermethylation of the promoter region of the MLH1 gene leads to loss of Mlh1 protein expression and plays a key role in the development of gastric cancer. Little is known about the association between Mlh1 expression and the clinicopathological and patient characteristics in early gastric neoplasia, particularly in endoscopically resected tumors. Immunohistochemistry was used to examine Mlh1 expression in 140 early gastric neoplasias obtained by endoscopic resection and comprising 31 gastric adenomas (GAs) and 109 early gastric cancers (EGCs), and compared them to corresponding clinicopathological and patient data. P53 expression and phenotypic profiles were also analyzed. The rate of reduced Mlh1 expression and P53 overexpression was 9.6 and 6.5% in GAs, and 27.5 and 27.5% in EGCs, respectively. In elderly patients (≥65 years of age), the aberrant expression of Mlh1 in EGCs was more significant in female than in male patients (59.9 vs. 29.8%; P=0.016). In addition, the frequency of aberrant Mlh1 expression in EGCs increased significantly in patients with oncological family histories and elevated gross type (P=0.033 and P=0.04, respectively). Moreover, a significant correlation was observed among aberrant Mlh1, P53-negative and HGM expression. The present findings suggest that loss of Mlh1 expression is associated with age, gender, oncological family history and tumor growth pattern in EGC. Patient and tumor characteristics are key factors in the screening, surveillance and diagnosis of early gastric neoplasia, particularly in elderly individuals.