P-146 Higher order relationships and the medicinal algorithmic combinatorial screen (MACS) (original) (raw)
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Prognostic significance of E-cadherin and β-catenin in resected stage I non-small cell lung cancer
European Journal of Cardio-Thoracic Surgery, 2003
Objectives: E-cadherin and its associated intracellular molecules, catenins, are important for cell-cell adhesion. Impaired expression of these molecules are frequently observed in several cancers. E-cadherin and b-catenin are often expressed in non-small cell lung cancers. The aim of this study was to investigate the expressions of E-cadherin and b-catenin and their significance as prognostic markers in pathological stage I non-small cell lung cancer. Methods: Paraffin embedded tumor tissue blocks were obtained from 141 patients who underwent resection without preoperative radiotherapy or chemotherapy with pathological stage I non-small cell lung cancer. Tumor samples were prepared in tissue microarrays and they were stained by immunohistochemistry with antibodies against E-cadherin and b-catenin. The expressions of E-cadherin and b-catenin were analyzed with relation to the clinico-pathological data. The median follow-up period of the patients was 41 months (range, 2 -88 months). Results: Preserved expressions of E-cadherin and b-catenin were observed in the membrane and the cytoplasm of normal epithelial cells and tumor cells. Absent or reduced expression for E-cadherin and b-catenin were observed in 60% and 45% of all the patients, respectively. There was a significant positive correlation between E-cadherin and b-catenin expression (P , 0:01). Absent or reduced expression of E-cadherin was observed in 72.5%, 36.6%, and 60.0% of squamous cell carcinoma, adenocarcinoma, and bronchioloalveolar carcinoma, respectively. There was a significant decrease of E-cadherin expression in squamous cell carcinoma compared to adenocarcinoma (P , 0:01). Patients with reduced expression of b-catenin had poor recurrence free survival in adenocarcinoma, but not in squamous cell carcinoma. Conclusion: Decreased expressions of E-cadherin and b-catenin were closely correlated in resected stage I non-small cell lung cancer. Reduced expression of E-cadherin and b-catenin indicates tumor cell dedifferentiation and reduced expression of b-catenin had poor recurrence free survival in adenocarcinoma of the resected stage I non-small cell lung cancer. q
Archivos de Bronconeumología, 2015
The aim of the Clinical and Molecular Staging of Stage I-IIp Lung Cancer Project is to identify molecular variables that improve the prognostic and predictive accuracy of TMN classification in stage I/IIp nonsmall cell lung cancer (NSCLC). Clinical data and lung tissue, tumor and blood samples will be collected from 3 patient cohorts created for this purpose. The prognostic protein signature will be validated from these samples, and micro-RNA, ALK, Ros1, Pdl-1, and TKT, TKTL1 y G6PD expression will be analyzed. Tissue inflammatory markers and stromal cell markers will also be analyzed. Methylation of p16, DAPK, RASSF1a, APC, and CDH13 genes in the tissue samples will be determined, and inflammatory markers in peripheral blood will be analyzed. Variables that improve the prognostic and predictive accuracy of TNM in NSCLC by molecular staging may be identified from this extensive analytical panel.
Modern Pathology, 2004
E-cadherin (E-cad) and epidermal growth factor receptor (EGFR) are important cell adhesion and signaling pathway mediators. This study aimed to assess their expression in lung adenocarcinoma (AdC) and squamous cell carcinoma (SCC) and their association with clinicopathologic variables. In all, 130 resectable lung cancers (stages I-IIIA) were studied using a high-density tissue microarray. Two to three cores from each case were arrayed into three blocks using a Beecher system. Immunohistochemistry was performed using an avidinbiotin complex method and monoclonal antibodies against E-cad and EGFR. Unequivocal membrane staining in 410% of tumor cells was considered as a positive expression of E-cad and EGFR. Markers expression and coexpression were analyzed against clinicopathologic variables (age, gender, smoking status, performance status, weight loss, histology, grade, stage, and lymph node involvement) and patient survival. There were 118, 126, and 115 cases that were fully assessable for E-cad, EGFR, and both markers, respectively. For E-cad, 65 cases (55%) were positive ( þ ), 53 (45%) were negative (À); 23 cases of the negative group had only cytoplasmic staining. For EGRF, 43 cases (34%) were ( þ ), and 83 (66%) were (À). There was no significant association between E-cad or EGFR, and any of the clinicopathologic variables except for an association between EGFR( þ ) and SCC histologic type. Both negative and cytoplasmic staining of E-cad correlated with shorter patient survival with P ¼ 0.008 and 0.002, respectively. EGFR expression did not correlate with patient survival; however, patients with E-cad(À)/EGFR( þ ) phenotype had poorer survival than those with E-cad( þ )/EGFR(À) (P ¼ 0.026). Our study suggests that lung AdC and SCC may be stratified based on expression of E-cad and EGFR with the E-cad(À)/EGFR( þ ) expression having a worse disease outcome. Moreover, the cytoplasmic expression of E-cad may represent an altered localization of this protein in association with tumorigenicity.
The expression of beta-catenin in non-small-cell lung cancer: a clinicopathological study
Journal of Clinical Pathology, 1998
Aims-To investigate the expression of -catenin in non-small-cell lung cancer (NSCLC) and its clinical significance. Methods-101 patients were surgically treated for NSCLC by lobectomy or pneumectomy with systematic lymph node dissection. Follow up was available in all patients, ranging from 24 to 110 months. Immunostaining of tissue sections from primary tumours and (when present) their lymph node metastases was performed and evaluated using a monoclonal antibody against -catenin. Correlations were investigated between -catenin immunostaining in primary tumours and E-cadherin immunostaining (data available from a previous study), lymph node stage, and survival. Results-There were significant correlations between scores for -catenin immunostaining and E-cadherin immunostaining in primary tumours (p = 0.007), and between the -catenin immunostaining score in primary tumours and in their lymph node metastases (p = 0.006). An inverse correlation was found between the -catenin immunostaining score in primary tumours and lymph node stage N0, N1, or N2 (p = 0.03). According to the Kaplan-Meier survival estimate, the level of -catenin expression in primary tumours was a statistically significant prognostic factor (p = 0.01). Conclusions-Reduced -catenin expression in surgically treated NSCLC is clearly associated with lymph node metastasis and an unfavourable prognosis. The existence of a functional relation between E-cadherin and -catenin is supported by the results of this clinicopathological study. (J Clin Pathol 1998;51:891-894) Downloaded from 1998 51: 891-894 J Clin Pathol J M Retera, M P Leers, M A Sulzer, et al. clinicopathological study. non-small-cell lung cancer: a The expression of beta-catenin in http://jcp.bmj.com/content/51/12/891
Journal of Thoracic Oncology, 2008
Purpose: To identify, in the international staging database of the International Association for the Study of Lung Cancer, those prognostic factors that were significant and independent of clinical stage. Material and Methods: From the data submitted to the staging data base concerning 100,869 patients, cases were selected for which all the following variables were available: clinical stage, age, gender, performance status (PS), and histologic cell types. For non-small cell lung cancer (NSCLC), 12,428 patients were assessable, and for SCLC, 6609 patients were available for this study. Methods used were Cox regression analyses and recursive partitioning and amalgamation analyses. Results: PS appeared to be a very important prognostic factor for survival in addition to clinical stage. Age and gender were other independent significant variables; For NSCLC and SCLC separately, recursive partitioning and amalgamation allowed the identification of four groups of patients with differing prognoses. In advanced NSCLC (stage IIIB / IV), some routine laboratory tests (mainly white blood cells and hypercalcaemia) were also found to be significant prognostic variables. In SCLC, albumin was an independent biologic prognostic factor.
Gene Expression Signatures for Predicting Prognosis of Squamous Cell and Adenocarcinomas of the Lung
Cancer Research, 2006
Non-small-cell lung cancers (NSCLC) compose 80% of all lung carcinomas with squamous cell carcinomas (SCC) and adenocarcinoma representing the majority of these tumors. Although patients with early-stage NSCLC typically have a better outcome, 35% to 50% will relapse within 5 years after surgical treatment. We have profiled primary squamous cell lung carcinomas from 129 patients using Affymetrix U133A gene chips. Unsupervised analysis revealed two clusters of SCC that had no correlation with tumor stage but had significantly different overall patient survival (P = 0.036). The high-risk cluster was most significantly associated with down-regulation of epidermal development genes. Cox proportional hazard models identified an optimal set of 50 prognostic mRNA transcripts using a 5-fold cross-validation procedure. Quantitative reverse transcription-PCR and immunohistochemistry using tissue microarrays were used to validate individual gene candidates. This signature was tested in an independent set of 36 SCC samples and achieved 84% specificity and 41% sensitivity with an overall predictive accuracy of 68%. Kaplan-Meier analysis showed clear stratification of high-risk and low-risk patients [log-rank P = 0.04; hazard ratio (HR), 2.66; 95% confidence interval (95% CI), 1.01-7.05]. Finally, we combined the SCC classifier with our previously identified adenocarcinoma prognostic signature and showed that the combined classifier had a predictive accuracy of 71% in 72 NSCLC samples also showing significant differences in overall survival (log-rank P = 0.0002; HR, 3.54; 95% CI, 1. 74-7.19). This prognostic signature could be used to identify patients with early-stage high-risk NSCLC who might benefit from adjuvant therapy following surgery. (Cancer Res 2006; 66(15): 7466-72)
Bangabandhu Sheikh Mujib Medical University Journal, 2023
Background: E-cadherin and Ki-67 expressions may provide real-me insights into the tumor's status and can be u lized as targeted therapeu cs for lung cancer. We aimed to explore the expression of Ki-67 and E-cadherin in non-small cell lung cancer (NSCLC) pa ents and to iden fy their associa on with clinicopathological features. Methods: In this cross-sec onal study, forty formalin-fixed paraffin-embedded (FFPE) NSCLC ssue blocks were iden fied from January to
Expression of the E-cadherin-catenin complex in lung neuroendocrine tumours
The Journal of Pathology, 2001
Neuroendocrine tumours (NETs) of the lung represent a wide spectrum of phenotypically distinct entities, with differences in tumour progression and aggressiveness. The redistribution and/or the loss of various cell adhesion molecules, such as the E-cadherin-catenin complex, play a predominant role in carcinogenesis and in tumour invasion. Moreover, mutations in exon 3 of the b-catenin gene, the adenomatous polyposis coli (APC) gene or the E-cadherin genes were previously found to result in intracytoplasmic and/or nuclear b-catenin protein accumulation, activating nuclear transcription of target genes involved in tumour progression. In the present study, the distribution of the components of this E-cadherin-catenin complex has been investigated by immunohistochemistry and an attempt has been made to correlate the abnormal expression pattern with the eventual detection of mutations in the corresponding genes. This study included 27 primary NETs of the lung, with nine typical carcinoids (TCs), three atypical carcinoids (ACs), and 15 large cell neuroendocrine carcinomas (LCNECs). The E-cadherincatenin complex remained expressed in most of these lung tumours, but with a cytoplasmic and/or nuclear redistribution of b-catenin, E-cadherin, and a-catenin; abnormal positive immunoreactivity was observed in 24 (88.9%), in 21 (80.8%), and in 20 (76.9%) NETs, respectively. In the great majority of cases, there was a good correlation between the expression of these three proteins, but no significant association with histological classification or TNM stage. Thus, E-cadherin-complex redistribution cannot be considered a prognostic marker in NET of the lung. Of particular interest was the frequent focal b-catenin nuclear immunostaining (55.5% in total), which was also unrelated to histological type or TNM stage. However, this study failed to detect any mutation in exon 3 of the b-catenin gene, in the APC gene or in the E-cadherin gene. These data suggest another mechanism of regulation of b-catenin in these tumours. E-cadherin-catenin complex to the actin cytoskeleton. b-catenin is a member of the armadillo (arm) family of proteins, acting as a component of the
Modern Pathology, 2000
Cyclins D 1 (cD 1) and E (cE) are G 1 phase cyclins believed to participate in the pathogenesis of malignancy. Overexpression of cD 1 has been reported to influence prognosis in squamous cell carcinomas (SCC) of the larynx, but was not significant in a limited study of non-small cell lung cancers (NSCLC). Altered expression of cE has been proposed as another potential prognostic marker in malignancy but its possible role in NSCLC has not been elucidated. In order to determine the prognostic value of cD 1 and cE in NSCLC, paraffinembedded sections of 467 NSCLC were immunostained with monoclonal antibody to cD 1 (1:500, PharMingen, San Diego, CA) and 400 NSCLC with MA to cE (1:2500, PharMingen) using an enhanced sensitivity avidin-biotin complex technique. The number of tumor cells with nuclear and/or cytoplasmic immunopositivity was graded on a scale of: 0 ؍ less than 1%, 1 ؍ 1 to 10%, 2 ؍ 10 to 25%, 3 ؍ 25 to 50%, 4 ؍ 50 to 75%, 5 ؍ more than 75%. Results were correlated with survival by Kaplan-Meier survival plot using Stat-View software (Abacus Concepts, Berkeley, CA). Overall, 426 NSCLC with cD 1 and 360 NSCLC with cE had adequate follow-up (median, 76 mo) for survival analysis. Both cyclins independently showed significance in prognosis of SCC but not other cell types. For cD 1 , absence of immunostaining was associated with worse prognosis than any immunopositivity for all stages of SCC (P ؍ .025). For cE, Stage I and II SCC with less than 50% immunopositivity had a worse prognosis (P ؍ .029). Of 70 Stage I and II SCC immunostained for both monoclonal antibodies, 55% of patients with tumors that demonstrated both absence of cD 1 staining and cE immunopositivity in less than 50% of cells were dead at 5 years compared to 35% of patients with tumors that demonstrated positive staining with cD 1 and cE immunopositivity in more than 50% of cells. These results strongly suggest cD 1 and cE can independently predict prognosis in early stage SCC. Worse prognosis was associated with loss of expression, consistent with mechanisms other than overexpression of these cyclins in the progression of SCC.
2023
Purpose: This study was performed to discover prognostic genomic markers associated with postoperative outcome of stage I to III non-small cell lung cancer (NSCLC) that are reproducible between geographically distant and demographically distinct patient populations. Experimental Design: American patients (n ¼ 27) were stratified on the basis of recurrence and microarray profiling of their tumors was performed to derive a training set of 44 genes. A larger Korean patient validation cohort (n ¼ 138) was also stratified by recurrence and screened for these genes. Four reproducible genes were identified and used to construct genomic and clinicogenomic Cox models for both cohorts. Results: Four genomic markers, DBN1 (drebrin 1), CACNB3 (calcium channel beta 3), FLAD1 (PP591; flavin adenine dinucleotide synthetase), and CCND2 (cyclin D2), exhibited highly significant differential expression in recurrent tumors in the training set (P < 0.001). In the validation set, DBN1, FLAD1 (PP591), and CACNB3 were significant by Cox univariate analysis (P 0.035), whereas only DBN1 was significant by multivariate analysis. Genomic and clinicogenomic models for recurrence-free survival (RFS) were equally effective for risk stratification of stage I to II or I to III patients (all models P < 0.0001). For stage I to II or I to III patients, 5-year RFS of the low-and high-risk patients was approximately 70% versus 30% for both models. The genomic model for overall survival of stage I to III patients was improved by addition of pT and pN stage (P < 0.0013 vs. 0.010). Conclusion: A 4-gene prognostic model incorporating the multivariate marker DBN1 exhibits potential clinical utility for risk stratification of stage I to III NSCLC patients. Clin Cancer Res; 17(9); 2934-46. Ó2011 AACR.