Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0001418 (adenocarcinoma)
68,496 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have used unbiased phosphoproteomic approaches, based on quantitative mass spectrometry using stable isotope labeling with amino acids in cell culture (SILAC), to identify tyrosine phosphorylated proteins in isogenic human bronchial epithelial cells (HBECs) and human lung adenocarcinoma cell lines, expressing either of the two mutant alleles of EGFR (L858R and Del E746-A750), or a mutant KRAS allele, which are common in human lung adenocarcinomas. Tyrosine phosphorylation of signaling molecules was greater in HBECs expressing the mutant EGFRs than in cells expressing WT EGFR or mutant KRAS. Receptor tyrosine kinases (such as EGFR, ERBB2, MET, and IGF1R), and Mig-6, an inhibitor of EGFR signaling, were more phosphorylated in HBECs expressing mutant EGFR than in cells expressing WT EGFR or mutant RAS. Phosphorylation of some proteins differed in the two EGFR mutant-expressing cells; for example, some cell junction proteins (beta-catenin, plakoglobin, and E-cadherin) were more phosphorylated in HBECs expressing L858R EGFR than in cells expressing Del EGFR. There were also differences in degree of phosphorylation at individual tyrosine sites within a protein; for example, a previously uncharacterized phosphorylation site in the nucleotide-binding loop of the kinase domains of EGFR (Y727), ERBB2 (Y735), or ERBB4 (Y733), is phosphorylated significantly more in HBECs expressing the deletion mutant than in cells expressing the wild type or L858R EGFR. Signaling molecules not previously implicated in ERBB signaling, such as polymerase transcript release factor (PTRF), were also phosphorylated in cells expressing mutant EGFR. Bayesian network analysis of these and other datasets revealed that PTRF might be a potentially important component of the ERBB signaling network.
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PMID:Comparisons of tyrosine phosphorylated proteins in cells expressing lung cancer-specific alleles of EGFR and KRAS. 1877 48

Cortactin, fascin-1 and EGFR are recognized as important factors in tumor progression. We tested the hypothesis that cortactin, fascin-1 and EGFR expression correlates with clinicopathological parameters of the four most common ovarian surface epithelial carcinomas--serous cystadenocarcinoma, mucinous cystadenocarcinoma, endometrioid adenocarcinoma, and clear cell carcinoma. Immunohistochemical analysis of cortactin, fascin-1 and EGFR was performed using tissue microarrays of 172 specimens comprising 69 serous cystadenocarcinomas, 44 mucinous cystadenocarcinomas, 45 endometrioid adenocarcinomas and 14 clear cell carcinomas. All ovarian carcinomas showed significant expression of cortactin, fascin-1 and EGFR in staining intensity, tumor percentages and immunostaining scores. In addition, higher immunostaining scores of fascin-1 correlated with more advanced cancer stages (TNM), poorer histological differentiation and poorer survival rate of mucinous cystadenocarcinoma. Similarly, higher immunostaining scores of cortactin correlated with T stages and histological differentiation of serous cystadenocarcinoma. The immunostaining scores of EGFR did not correlate with TNM stages, tumor differentiation or prognosis in the four ovarian surface epithelial carcinomas. Our findings suggest that cortactin and fascin-1 may serve as good biomarkers in evaluating aggressiveness of ovarian serous and mucinous cystadenocarcinoma. And the pharmacological inhibitors of fascin-1 activity may slow down tumor progression and prolong survival time in patients with mucinous cystadenocarcinoma.
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PMID:Association of cortactin, fascin-1 and epidermal growth factor receptor (EGFR) expression in ovarian carcinomas: correlation with clinicopathological parameters. 1877 88

It has been suggested that a high EGFR gene copy number may be an indicator of good response to EGFR tyrosine kinase inhibitor therapy and a marker of poor prognosis in NSCLC. However, imaging features related to EGFR gene copy number status in adenocarcinoma are still unknown. We therefore retrospectively analyzed CT, FDG-PET, and histopathologic slides of surgical resected lung adenocarcinoma in 132 patients. Tumor characteristics on preoperative chest-CT, such as, GGO proportions, tumor diameters, and cavitation; FDG-PET SUV(max); and histopathologically determined differentiation degrees and tumor subtypes were evaluated. EGFR gene copy number status was categorized as FISH-positive or -negative. FISH-positivity was found in 53 patients (40.2%) and was significantly more frequent in tumors with a SUV(max)>7.0 (P=0.007). Furthermore, FISH-negativity was found to be more frequent in tumors with a GGO>50% (P=0.023) and diameter <15.5mm (P=0.006) on CT, or a well-differentiated histopathology (P=0.002). Moreover, the frequency of FISH-positivity increased as SUV(max) increased (P=0.0008) and as the proportion of GGO decreased (P=0.01). SUV(max)>7.0 was an independent predictor of FISH-positive results (odds ratio, 3.941; 95% CI, 1.691-9.182; P=0.01). In conclusion, a high SUV(max) on FDG-PET was significantly related to FISH-positive results. A high proportion of GGO, small tumor diameter on CT, and a well-differentiated histopathology were more frequent in FISH-negative adenocarcinomas.
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PMID:EGFR gene copy number in adenocarcinoma of the lung by FISH analysis: investigation of significantly related factors on CT, FDG-PET, and histopathology. 1881 24

The incidence of several extracolonic tumors, such as duodenal carcinoma, is higher in familial adenomatous polyposis (FAP) patients than in the general population, but there is little information about lung carcinoma in FAP. A 43-year-old woman presented with a lung tumor 17 years after total colectomy for FAP. Pathohistological analysis of the lung tumor demonstrated mixed adenocarcinoma consisting of a papillary adenocarcinoma component and a bronchioloalveolar carcinoma component. Sequencing analysis indicated a germline APC mutation from TCA to TGA (stop) at codon 1110, but no pathogenic germline MYH mutations. The other APC allele in the lung carcinoma was not inactivated by somatic mutations, promoter methylation, or chromosomal deletion. No somatic mutations in any of the coding regions of the p53 gene or in the mutation hot spot regions of the K-ras or EGFR genes were detected in the carcinoma. Amplification, however, of three chromosome regions, 5p, 8q, and 12q14-12q21, was identified in the carcinoma on genome-wide high-resolution single-nucleotide polymorphism (SNP) microarray. The present results suggest that the chromosomal copy number alterations detected on SNP microarray were involved in the carcinogenesis of the adenocarcinoma of the lung in the present FAP patient.
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PMID:Characterization of adenocarcinoma of the lung in a familial adenomatous polyposis patient. 1884 36

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
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PMID:Somatic mutations affect key pathways in lung adenocarcinoma. 1894 47

EGFR (ErbB1) and ErbB2 receptors stimulate several intracellular signaling pathways in non-small-cell lung cancer (NSCLC). Adenocarcinomas (AC) and squamous cell carcinomas (SCC) are NSCLC subtypes with distinct clinico-pathological features, and responses to ErbB-targeted inhibitors treatment. To evaluate the causes of these differences, tissue microarrays with samples from NSCLC patients (189 AC and 56 SCC) were used to study EGFR and ErbB2 expression and phospho-activation of ERK1/2, AKT, STAT3 and SRC ErbB-mediators by immunohistochemistry and Western blot, and EGFR and ErbB2 gene amplification by FISH. EGFR expression was higher in SCC than in AC (P<0.001), while ErbB2 showed similar low levels. Phosphorylated (p) ERK, pAKT, pSTAT3 and pSRC levels were prevalent in AC (P< or =0.002). EGFR levels and signaling mediators activation were differentially associated with each of the pathologies. Whereas in AC the expression and amplification of EGFR were linked to AKT activation (P< or =0.050), in SCC its expression was correlated with pSTAT3 (P=0.024). In addition, pSTAT3 was correlated with pERK and pAKT only in AC (P< or =0.045). Biomarker levels were also differentially associated with the clinico-pathologic variables. In AC, EGFR and pSRC increasing scores correlated with female sex and the smoking habit (P< or =0.008), while ErbB2 amplification increased with advanced age and tumor stage (P< or =0.047), and pERK1/2 and pSTAT3 levels correlated with early tumor stage (P< or =0.045). In SCC, EGFR amplification was stronger in younger patients (P=0.013), pERK1/2 in the older ones (P=0.050), and pSTAT3 amplification was stronger in women (P=0.001). These data support that AC and SCC lung tumors are distinct entities at the molecular level, and that their signaling status in combination with their clinico-pathologic variables may be considered for differential targeted therapies.
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PMID:Differential ErbB receptor expression and intracellular signaling activity in lung adenocarcinomas and squamous cell carcinomas. 1904 92

Gefitinib is a molecular targeting agent and more effective in patients with characteristics of oriental ethnicity, female gender, adenocarcinoma and non-smokers. It is sometimes effective in smokers, but few papers have focused on the association between efficacy and smoking history. The aim of this study is to evaluate the association between efficacy of gefitinib and patients' characteristics, especially smoking history. Between July 2002 and September 2006, 89 patients were diagnosed as non-small cell lung cancer and administered gefitinib. Eighty of them were assessable for efficacy and toxicity of gefitinib. Response rate was 16.2% and 39.6%(p=0.031)in smokers and non-smokers. Survival was statistically greater in non-smokers. In smokers, there are more cases which showed response to gefitinib with a lower smoking index and longer duration after smoking cessation. Smoking index and duration after smoking cessation should be considered when gefitinib is administered or EGFR mutation analysis is conducted in patients with non-small cell lung cancer.
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PMID:[Efficacy of gefitinib according to smoking status in non-small cell lung cancer patients]. 1909 4

Gefitinib is an orally bioavailable, EGF receptor tyrosine kinase inhibitor and was the first targeted drug to be approved for non-small-cell lung cancer (NSCLC). Identification of objective tumor regressions with gefitinib in NSCLC patients has resulted in intense, worldwide clinical and basic research directed toward finding the optimal use of gefitinib in NSCLC. A recent large international Phase III study (IRESSA NSCLC Trial Evaluating Response and Survival Against Taxotere [INTEREST]) comparing gefitinib and docetaxel in unselected pretreated patients showed equivalent survival with better tolerability and quality of life. In addition, a Phase III study (WJTOG0203) evaluating gefitinib as sequential therapy after platinum-doublet chemotherapy showed the improved progression-free survival time. Furthermore, a large-scale randomized study (IRESSA Pan-Asia study [IPASS]) comparing gefitinib monotherapy with carboplatin/paclitaxel for previously untreated patients with adenocarcinoma who were never- or light-smokers showed an improved progression-free survival time in the gefitinib arm. A smaller Phase III study of pretreated Japanese patients (V-15-32) also demonstrated no difference in overall survival compared with docetaxel, with a statistically greater overall response rate. Somatic mutations in the EGFR gene, the target of gefitinib, were associated with dramatic and durable regressions in patients with NSCLC. Currently, investigators are trying to determine the optimal approach to select patients for treatment with gefitinib. This article aims to briefly summarize the profile of gefitinib, EGFR mutations, landmark trials with gefitinib and, also, ongoing trials that may herald an era of individualized therapy in at least some NSCLC patients.
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PMID:Gefitinib for the treatment of non-small-cell lung cancer. 1910 4

The expression of epidermal growth factor receptors in normal and tumor cells of the pancreas, the type and incidence of EGFR gene polymorphism were studied. EGFR gene expression in pancreatic adenocarcinoma cells significantly surpassed that in normal pancreatic cells. On the other hand, AA genome and A allele polymorphism in the EGF gene nucleotide pair G-A 61 is a significant risk factor for pancreatic cancer. The effect of AG-1478 preparation (a new-generation inhibitor of EGFR) on apoptosis and cell proliferation in pancreatic cancer was evaluated. This preparation is not inferior to 5FU by its apoptotic effect and significantly reduces cell proliferation, its antiproliferative effect being 1.5 times higher than that of 5FU.
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PMID:Role of epidermal growth factor gene in the development of pancreatic cancer and efficiency of inhibitors of this gene in the treatment of pancreatic carcinoma. 1911 Jun 11

We examined the methylation status in 100 specimens of lung adenocarcinomas measuring 2cm or less and with bronchioloalveolar carcinoma (BAC) components (Noguchi types A-C) and then compared the methylation status between noninvasive tumors (Noguchi type A or B) and invasive tumors (Noguchi type C). Methylation-specific PCR was used to determine the methylation statuses of p16(INK4a), RASSF1A, CDH13, RARbeta, and Cyclin D2. The methylation index that was regarded as representing the degree of methylation was calculated. We also determined the mutational statuses of EGFR exons 19 and 21 using a PCR-based method. A multivariate analysis showed that the aberrant methylation of p16(INK4a), RASSF1A, and CDH13 was significantly more frequent in invasive tumors than in noninvasive tumors [p16(INK4a), 36.5% versus (vs.) 8.3%, P=0.0023; RASSF1A, 46.2% vs. 14.6%, P=0.0012; CDH13, 42.3% vs. 10.4%, P=0.0006]. The methylation index was significantly higher in invasive tumors than in noninvasive tumors (P=0.004). The methylation of p16(INK4a) was significantly more frequent in EGFR wild-type tumors than in EGFR mutant tumors (P=0.021). Our results indicate the involvement of epigenetic alterations in the progression of adenocarcinoma with BAC components.
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PMID:DNA methylation in small lung adenocarcinoma with bronchioloalveolar carcinoma components. 1914 41


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