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Molecular Analyses of Early-Onset Gastric Cancer in Brazilian Patients: TP53 Mutations, Cadherin-Catenin and Mucins Proteins Expression  [PDF]
Edaise Maria da Silva, José Humberto Tavares Guerreiro Fregnani, Ghyslaine Martel, Wilson Luiz Costa Jr., Felipe José Fernández Coimbra, Maria Isabel Waddington Achatz, Pierre Hainaut, Fernando Augusto Soares
Journal of Cancer Therapy (JCT) , 2013, DOI: 10.4236/jct.2013.41A005

Early gastric carcinomas may develop with a molecular profile differing from sporadic carcinomas occurring at a later age. In this study, we analyzed a retrospective series of 88 patients with gastric adenocarcinoma diagnosed before the age of 45 years for the presence of TP53 mutations, clinicopathological features and immunohistochemistry to evaluate the expression of markers considered to be important in gastric carcinogenesis (E-cadherin, β-catenin, MUC1, MUC2, MUC5AC, MUC6 and p53). The majority of proportion of tumors were diffuse-type (70%) and advanced stage (56%). Familial history of cancer was positive in 21% of the cases. There was a significant association between altered expression of E-cadherin and β-catenin, and between p53 expression and perineural invasion. TP53 mutations were detected in 14.5% of evaluated cases, including a germline mutation (p.R337H) in a 12-year old patient. Overall survival analysis showed significant differences in relation with tumor stage and histopathology. The evaluated biomarkers did not present prognostic value in non-exploratory multivariate analyses. The low frequency of TP53 mutations in this series suggests these alterations are not a major molecular event in gastric cancer occurring at early age, although the identification of a case with germline p.R337H mutation is consistent with the hypothesis that a small proportion of early, apparently sporadic gastric cancer, may be associated with widespread Brazilian founder mutations. Further studies are needed to evaluate the prognostic significance of markers for specific groups of patients according to tumor histology and familial history.

Alterations of E-cadherin and β-catenin in gastric cancer
Chen Huiping, Sigrun Kristjansdottir, Jon G Jonasson, Jonas Magnusson, Valgardur Egilsson, Sigurdur Ingvarsson
BMC Cancer , 2001, DOI: 10.1186/1471-2407-1-16
Abstract: We studied the alterations of E-cadherin and β-catenin in a set of 50 primary gastric tumours by using loss of heterozygosity (LOH) analysis, gene mutation screening, detection of aberrant transcripts and immunohistochemistry (IHC).A high frequency (75%) of LOH was detected at 16q22.1 containing E-cadherin locus. Three cases (6%) showed the identical missense mutation, A592T. This mutation is not likely to contribute strongly to the carcinogenesis of gastric cancer, because a low frequency (1.6%) of this mutation was also found in 187 normal individuals. We also detected a low frequency (0.36%, 0%) of this mutation in 280 breast tumours and 444 other tumours, including colon and rectum, lung, endometrium, ovary, testis, kidney, thyroid carcinomas and sarcomas, respectively. We also analyzed the aberrant E-cadherin mRNAs in the gastric tumours and found that 7 tumours (18%) had aberrant mRNAs in addition to the normal mRNA. These aberrant mRNAs may produce abnormal E-cadherin molecules, resulting in weak cell-cell adhesion and invasive behaviour of carcinoma cells. Reduced expression of E-cadherin and β-catenin was identified at the frequency of 42% and 28%, respectively. Specially, 11 tumours (22%) exhibited positive cytoplasmic staining for β-catenin IHC. An association was found between reduced expression of E-cadherin and β-catenin. Moreover, an association was detected between reduced expression of E-cadherin and diffuse histotype.Our results support the hypothesis that alterations of E-cadherin and β-catenin play a role in the initiation and progression of gastric cancer.E-cadherin (120 kDa; chromosome 16q) is a classical cadherin and forms the key functional component of adherence junctions between epithelial cells [1]. It is bound via a series of undercoat proteins, the catenins (α, β and γ) to the actin cytoskeleton [1]. This linkage between transmembranous cadherins and actin filaments of the cytoskeleton is necessary to form strong cell-cell adhesion. An i
Clinicopathological significance of E-cadherin, !-catenin and p53 expression in gastric adenocarinoma  [cached]
Mohammad Reza Zali,Omeed Moaven,Hamid Reza Asadzadeh Aghdaee,Kamran Ghafarzadegan
Journal of Research in Medical Sciences , 2009,
Abstract: BACKGROUND: E-cadherin/catenin complexes exert a role in cell adhesion. '-catenin is a key player in Wnt signaling pathway in gastric cancer. P53 is a tumor suppressor gene which also regulates apoptosis. We assessed the expression of E-cadherin, '-catenin and p53 in gastric adenocarcinoma, and their correlations with linicopathological features. METHODS: Fifty six formalin-fixed, paraffin-embedded archival specimens of gastric adenocarcinoma were andomly included as cases. Adjacent tumor-free gastric mucosa of different premalignant stages was obtained from the cases. Immunohistochemical staining was performed to assess E-cadherin, '-catenin and p53 expression. RESULTS: All chronic atrophic gastritis and intestinal metaplasia revealed normal membranous staining. Only one patient with dysplasia had abnormal expression of E-cadherin and '-Catenin. Abnormal E-cadherin, '-catenin and p53 expression was found in 50%, 48.2% and 76.8% of cancer specimens respectively. Abnormal expression of E-cadherin was significantly correlated with aberrant '-catenin expression. Abnormal E-cadherin and '-catenin expression were significantly correlated with depth of tumor invasion and advanced gastric cancer (p < 0.05), lower degree of differentiation and diffused tumor type (p < 0.001). Node metastasis was not influenced by abnormal expression of E-cadherin and '-catenin. P53 was not associated with clinicopathological variables.
The expression of E-cadherin-catenin complex in patients with advanced gastric cancer: role in formation of metastasis.  [cached]
Jolanta Czyzewska,Katarzyna Guzińska-Ustymowicz,Marek Ustymowicz,Anna Pryczynicz
Folia Histochemica et Cytobiologica , 2010, DOI: 10.5603/4257
Abstract: The E-cadherin-catenin complex plays an important role in the process of cell adhesion. Its dysfunction is associated with a decrease in cell differentiation and with increased invasiveness and metastasis. Our aim was to evaluate the expression of E-cadherin and B-catenin in advanced gastric cancer in relation to selected clinico-pathomorphological parameters. Formalin-fixed, paraffin-embedded tissue specimens were immunohistochemically stained with monoclonal antibodies E-cadherin (NCL-E-Cad, Novocastra Laboratiries Ltd; dilution 1:50), beta-catenin (NCL-B-CAT, Novocastra Laboratories Ltd; dilution 1:100), alpha-catenin (alpha-E-caten, Santa Cruz Biotechnology; dilution 1:300) and gamma-catenin (gamma-catenin, Santa Cruz Biotechnology; dilution 1:100). The expressions of E-cadherin and alpha-, beta-, gamma-catenins in the main mass of tumor and lymph node metastasis were investigated in 91 patients with gastric cancer. No statistically significant correlation was observed between the expressions of E-cadherin, alpha-, beta-catenins and histological differentiation and between the expressions of E-cadherin, alpha-, gamma-catenins and location or depth of invasion. Moreover, the expression of alpha-, gamma-catenins in the main mass of tumor was not associated with lymph node metastasis. However, we found a relationship between the expression of beta-catenin in the main mass of tumor and lymph node metastasis and tumor location. The depth of invasion was correlated with positive expression of beta-catenin in the main mass of gastric cancer. A statistically significant association was observed between the expressions of E-cadherin and beta-catenin in the main mass of tumor and lymph node involvement. The expression of alpha-catenin in the main mass of tumor was also associated with histological differentiation and Lauren's classification. Statistical analysis showed an association between the expression of E-cadherin and postoperative survival time. No significant correlation was found between the expression of alpha-, beta-, gamma-catenins and survival time. Our results may suggest that the E-cadherin-catenin complex is the factor indicative of metastasis and disease progression in gastric cancer. Also the expression of E-cadherin may play a role as a prognostic factor.
Expresión inmunohistoquímica del complejo E-caderina-catenina en cáncer gástrico: Relación con variables clínico-morfológicas y sobrevida de pacientes Immunohistochemical expression of the E-cadherin-catenin complex in gastric cancer  [cached]
Pablo Guzmán G,Juan Araya O,Miguel Villaseca H,Iván Roa E
Revista médica de Chile , 2006,
Abstract: Background: The E-cadherin/catenin complex plays an essential role in the control of epithelial differentiation. Abnormal expression in tumors correlates with histological grade, advanced stage and poor prognosis. Aim: To evaluate the expression pattern of E-cadherin/catenin complex in gastric carcinoma and analyze their association with tumor clinicopathological features and patient survival. Material and Methods: Inmunohistochemical staining of E-cadherin, alpha and -catenin was performed from paraffin specimens of 65 gastric carcinomas. Results: Abnormal expression of E-cadherin, alpha and -catenin was demonstrated in 82%, 85% and 88% of gastric carcinomas, respectively. There was a significant correlation between abnormal expression and Lauren pathological classification and depth of infiltration, but not with tumor stage, positive lymph node metastases and survival. Conclusion: Abnormal expression of E-cadherin, alpha and -catenin occurs frequently in gastric carcinoma and correlates with histological grade (Rev Méd Chile 2006; 134: 1002-9).
E-Cadherin/β-Catenin Complex and the Epithelial Barrier
Xinrui Tian,Zhuola Liu,Bo Niu,Jianlin Zhang,Thian Kui Tan,So Ra Lee,Ye Zhao,David C. H. Harris,Guoping Zheng
Journal of Biomedicine and Biotechnology , 2011, DOI: 10.1155/2011/567305
Abstract: E-Cadherin/β-catenin complex plays an important role in maintaining epithelial integrity and disrupting this complex affect not only the adhesive repertoire of a cell, but also the Wnt-signaling pathway. Aberrant expression of the complex is associated with a wide variety of human malignancies and disorders of fibrosis resulting from epithelial-mesenchymal transition. These associations provide insights into the complexity that is likely responsible for the fibrosis/tumor suppressive action of E-cadherin/β-catenin.
TP53 and Beta-catenin mutations in liver tumours
Pierre Hainaut
Iatreia , 2007,
Abstract: HBV and HCV play key roles in the etiopathogenesis of Hepatocellular carcinoma (HCC) . Studies mostly based on cases from Western countries suggest distinct genetic pathways of carcinogenesis involving either TP53 or CTTNB1 mutations. Inappropriate reactivation of Wnt pathway due to mutations in CTNNB1 (Beta-Catenin) gene itself is also frequently reported. Mutant Beta-catenin escapes to ubiquitination and down regulation by GSK3-B, it accumulates and trans-activates variety of oncogenes involved in neoplasmic transformation mimicking Wnt pathway activation. Taking into consideration viral infection, chromosome instability and TP53 /Beta-catenin alterations, Laurent-Puig et al. described two distinct HCC profiles in a serie of 137 HCC cases , the first one associates HBV infection with frequent chromosomal alteration and distributes with TP53 mutations, the second would be observed in HBV negative large sized tumors and distributes with Beta-catenin mutations. We have investigated the status of HBV and HCV infections and of genetic alterations in TP53 and CTTNB1 in 26 patients with HCC from Thailand. In tumours, HBV DNA was found in 19 cases (73%) and HCV RNA in 4 cases (15.4% cases), 3 of whom were co-infected. Among the 19 HBV positive cases, sequencing of S gene showed genotype C in 82% and genotype B in 18%. Furthermore, 5/19 cases were negative for HBsAg and were categorized as occult HBV infections. TP53 mutations were detected in 9 cases (34,6%) including 7 mutations at codon 249 (AGG to AGT, arginine to serine), considered as ";fingerprint"; of mutagenesis by aflatoxin metabolites. All cases with 249ser mutation had overt HBV infection. CTNNB1 mutations were found in 6/26 cases (23%), 4 of whom also had TP53 mutation. There was no significant association between CTTNB1 mutations and viral infection status. These results suggest that mutagenesis by aflatoxin may have an impact greater than recognized sofar in the etiopathogenesis of HCC in Thailand. Furthermore, TP53 and CTNNB1 mutations do not appear as mutually exclusive, and TP53 249ser mutation is associated with overt HBV infection. Thus, HCC in this context may develop according to a sequence of genetic events that includes both TP53 and CTNNB1 mutations.
Reduced expression of E-cadherin/catenin complex in hepatocellular carcinomas  [cached]
Bo Zhai, He-Xin Yan, Shu-Qin Liu, Lei Chen, Meng-Chao Wu, Hong-Yang Wang
World Journal of Gastroenterology , 2008,
Abstract: AIM: To examine the immunoreactivity of E-cadherin and four subtypes of catenin family in human hepatocellular carcinomas (HCCs) and to investigate the correlation between expression of E-cadherin/catenin complex and clinicopathologic parameters of HCC patients.METHODS: An immunohistochemical study for E-cadherin and catenins was performed on 97 formalin-fixed, paraffin-embedded specimens of HCC.RESULTS: Reduced expression of E-cadherin, α-, β-, γ-catenin and p120 was observed in 69%, 76%, 63%, 71% and 73%, respectively. Both expressions of E-cadherin and catenin components were significantly correlated with tumor grade (P = 0.000). It showed significant difference between expression of catenin members and tumor stage (P = 0.003, P = 0.017, P = 0.007 and P = 0.000, respectively). The reduced expression of E-cadherin in HCCs was significantly correlated with intrahepatic metastasis (IM) and capsular invasion (P = 0.008, P = 0.03, respectively). A close correlation was also observed between the expression of catenins and the tumor size (P = 0.002, P = 0.034, P = 0.016 and P = 0.000, respectively). In addition, the expression of each catenin was found correlated with IM (P = 0.012, P = 0.049, P = 0.026 and P = 0.014, respectively). No statistically significant difference was observed between the expression level of E-cadherin/catenin complex and lymph node permission, vascular invasion and satellite nodules. Interestingly, only expression of p120 showed correlation with AFP value (P = 0.035). The expression of E-cadherin was consistent with α-, β-, γ-catenin and p120 expression (P = 0.000). Finally, the abnormal expression of E-cadherin/catenin complex was significantly associated with patients’ survival (P = 0.0253, P = 0.0052, P = 0.003, P = 0.0105 and P = 0.0016, respectively). Nevertheless, no component of E-cadherin/catenin complex was the independent prognostic factor of HCC patients.CONCLUSION: Down-regulated expressions of E-cadherin, catenins and p120 occur frequently in HCCs and contribute to the progression and development of tumor. It may be more exact and valuable to detect the co-expression of E-cadherin/catenin complex than to explore one of them in predicting tumor invasion, metastasis and patient’s survival.
Cadherin-Bound β-Catenin Feeds into the Wnt Pathway upon Adherens Junctions Dissociation: Evidence for an Intersection between β-Catenin Pools  [PDF]
Yoonseok Kam, Vito Quaranta
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004580
Abstract: β-catenin is an essential component of two cellular systems: cadherin-based adherens junctions (AJ) and the Wnt signaling pathway. A functional or physical connection between these β-catenin pools has been suggested in previous studies, but not conclusively demonstrated to date. To further examine this intersection, we treated A431 cell colonies with lysophosphatidic acid (LPA), which forces rapid and synchronized dissociation of AJ. A combination of immunostaining, time-lapse microscopy using photoactivatable-GFP-tagged β-catenin, and image analyses indicate that the cadherin-bound pool of β-catenin, internalized together with E-cadherin, accumulates at the perinuclear endocytic recycling compartment (ERC) upon AJ dissociation, and can be translocated into the cell nucleus upon Wnt pathway activation. These results suggest that the ERC may be a site of residence for β-catenin destined to enter the nucleus, and that dissociation of AJ may influence β-catenin levels in the ERC, effectively affecting β-catenin substrate levels available downstream for the Wnt pathway. This intersection provides a mechanism for integrating cell-cell adhesion with Wnt signaling and could be critical in developmental and cancer processes that rely on β-catenin-dependent gene expression.
Inmunohistochemical expression of p53, Bcl-2, COX-2, C-erb-B2, EPO-R, ?-catenin, and E-cadherin in non tumoral gastric mucous membrane  [cached]
M Sereno,MA García-Cabezas,J De Castro,P Cejas
European Journal of Histochemistry , 2006, DOI: 10.4081/998
Abstract: Different authors have investigated the immunohistochemical expression of some proteins in the adenocarcinoma of the stomach, including cell cycle regulators proteins like p53 and Bcl-2; growth factors (c-erb-B2 and EPO-R); angiogenesis- related markers such as COX-2 and cellular adhesion molecules (?-catenin and E-cadherin). While these proteins have been studied in gastric adenocarcinoma, their immunophenotyping in non tumoral gastric mucous membrane remains unexplored. In the present study, we investigated the expression, function and behavior of these proteins in normal gastric mucous membrane to contribute to gain further knowledge on the significance of their loss or overexpression in malignant gastric tumors.
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