Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001418 (adenocarcinoma)
 68,496 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atypical adenomatous hyperplasia (AAH) is considered the preinvasive lesion of pulmonary adenocarcinoma, and mutations of EGFR, HER2, and K-ras are involved in the early stage of lung adenocarcinoma carcinogenesis, also predicting clinical response to anti-EGFR small molecule inhibitors. We analyzed 18 cases of primary lung adenocarcinoma with concomitant AAH foci from 13 patients for mutations of EGFR (exons 18-21), HER2 (exons 19-20), and K-ras (exon 2) by direct sequencing polymerase chain reaction. Among mutated cases, concordant mutations of EGFR or K-ras in adenocarcinoma and related AAH were observed in 5 (63%) of 8 cases. In particular, 3 of 4 adenocarcinomas with EGFR mutations (all L858R point mutations in women, never or former smokers) had a concomitant and identical mutation in AAH, and 2 of 4 adenocarcinomas with K-ras mutations (both at codon 12 in women, a never and a current smoker) showed the same mutation in concomitant AAH. All cases were wild-type for HER2. Mutations of EGFR and K-ras genes represent an early event in lung adenocarcinomagenesis, and AAH convincingly seems to be a precursor lesion in a subset of cases of adenocarcinoma.
 ...
PMID:A subset of lung adenocarcinomas and atypical adenomatous hyperplasia-associated foci are genotypically related: an EGFR, HER2, and K-ras mutational analysis. 1869 92

EGFR is a tyrosine kinase (TK) receptor overexpressed in lung adenocarcinomas. EGF binding to EGFR leads to K-Ras activation, promoting signaling of division, survival, and cell invasion. Adenocarcinomas addicted to EGFR signaling pathway for proliferation (10%), exhibit mutations of EGFR tyrosine kinase domain. Inhibition of these mutated receptors favors apoptosis signaling, taking account for dramatic tumoral responses. On the other side, 30% of adenocarcinomas have K-Ras mutations making the cells resistant to EGFR TK inhibitors (TKI). Secondary resistances are induced in 50% of initially sensitive tumors by an additional EGFR mutation (T790M), lowering receptor affinity for the inhibitor. The use of high affinity inhibitors ("irreversible") is tested in those patients. In 30% of cases, secondary resistance to TKI is induced by amplification of C-Met gene that encodes for another TK receptor, stimulating cell survival by substitution to EGFR. The use of C-Met inhibitors could overcome this kind of resistance. Angiogenesis is an early event in lung cell cancerization of which main cell signaling uses TK receptors to VEGF. Inhibition of this pathway consists in a major therapeutic advance in solid tumors. Finally, stimulation of anti-tumoral immunological response using anti-tumoral "vaccination", or agonists of innate immunity receptors, has given encouraging therapeutic preliminary results in lung cancer but needs phase 3 validation trials.
 ...
PMID:[Mechanisms of action of targeted therapies... and mechanisms of resistance]. 1823 12

EML4-ALK gene fusions have recently been discovered in a subset of human lung carcinomas, and fusions of the ALK tyrosine kinase gene with the NPM, TPM3, CLTC, ATIC, and TFG genes have been found in hematological malignancies. To elucidate the role of fusions between ALK and other genes in pulmonary carcinogenesis, we examined 77 non-small cell lung carcinomas (NSCLCs) for EML4-, NPM-, TPM3-, CLTC-, ATIC-, and TFG-ALK fusion transcripts by RT-PCR and subsequent sequencing analysis. Although no expression of NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts were detected in any of the cases, expression of EML4-ALK fusion transcripts was detected in two (2.6%) of the 77 NSCLCs. In one of the two NSCLCs there was fusion between exon 13 of EML4 and exon 20 of ALK, i.e., variant 1, and in the other there was fusion between exon 20 of EML4 and exon 20 of ALK, i.e., variant 2. Both patients had a history of smoking, and histologically the carcinomas were adenocarcinoma. No somatic mutations were detected in the mutation cluster regions of the EGFR, K-RAS, and PIK3CA genes in these two carcinomas, however, a Pro177Ser mutation of the p53 gene was detected in the carcinoma that contained the variant 1 EML4-ALK fusion transcripts. In situ PCR of a paraffin block section showed that the carcinoma with expression of the variant 1 actually contained an EML4-ALK fusion gene. These results suggested that the EML4-ALK fusion gene product is involved in the carcinogenesis of a subset of NSCLCs.
 ...
PMID:EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas. 1824 62

A total of 211 cases of primary lung adenocarcinoma were tested for expression of gross cystic disease fluid protein-15 (GCDFP-15) and only 11 cases (5.2%) were positive. The cases occurred with an equal sex distribution in older individuals whose carcinomas were frequently identified on screening radiographs. The adenocarcinomas were peripheral lesions and had an average size of 2.9 cm (range, 1.1 to 7.0). Histologically, they were usually mixed acinar and papillary adenocarcinomas with abundant extracellular mucin production, with the neoplastic cells having a polygonal shape, round to oval nuclei, diffuse powdery chromatin, and abundant eosinophilic granular cytoplasm. Clear cells and apocrinelike cells with prominent central nucleoli were common. GCDFP-15 was expressed in conjunction with thyroid transcription factor-1 in 81% of cases and synaptophysin was seen in 65%. Estrogen and progesterone receptors were not expressed. EGFR gene amplification and mutations of exons 19 and 21 were rare. KRAS mutations and HER2 gene amplification were not seen. This report details the first 11 cases of pulmonary adenocarcinoma to express GCDFP-15 and their distinctive morphology with frequent mucin production and coexpression of thyroid transcription factor-1 and synaptophysin.
 ...
PMID:Gross cystic disease fluid protein-(GCDFP-15): expression in primary lung adenocarcinoma. 1830 Aug 7

Except in developed countries, the incidence of lung cancer notably in women and non-smokers is rising in most parts of the world. Here, we report two children diagnosed with pulmonary adenocarcinoma at a very early age. Interestingly, both showed negative EGFR mutation despite their ethnicity, histology, never smoking status and early age. Furthermore, one had preceding pulmonary tuberculosis. In the literature, the possible association of pulmonary tuberculosis and adenocarcinoma of lung especially in non-smokers has long been debated. The two children, by far the youngest with EGFR negative adenocarcinoma of lung, form the basis of this report.
 ...
PMID:Adenocarcinoma of lung in never smoked children. 1839 48

Receptor tyrosine kinases (RTK) are therapeutic targets for the treatment of malignancy. However, tumor cells develop resistance to targeted therapies through the activation of parallel signaling cascades. Recent evidence has shown that redundant or compensatory survival signals responsible for resistance are initiated by nontargeted glycoprotein RTKs coexpressed by the cell. We hypothesized that disrupting specific functions of the posttranslational machinery of the secretory pathway would be an effective strategy to target both primary and redundant RTK signaling. Using the N-linked glycosylation inhibitor, tunicamycin, we show that expression levels of several RTKS (EGFR, ErbB2, ErbB3, and IGF-IR) are exquisitely sensitive to inhibition of N-linked glycosylation. Disrupting this synthetic process reduces both cellular protein levels and receptor activity in tumor cells through retention of the receptors in the endoplasmic reticulum/Golgi compartments. Using U251 glioma and BXPC3 pancreatic adenocarcinoma cell lines, two cell lines resistant to epidermal growth factor receptor-targeted therapies, we show that inhibiting N-linked glycosylation markedly reduces RTK signaling through Akt and radiosensitizes tumor cells. In comparison, experiments in nontransformed cells showed neither a reduction in RTK-dependent signaling nor an enhancement in radiosensitivity, suggesting the potential for a therapeutic ratio between tumors and normal tissues. This study provides evidence that enzymatic steps regulating N-linked glycosylation are novel targets for developing approaches to sensitize tumor cells to cytotoxic therapies.
 ...
PMID:Inhibition of N-linked glycosylation disrupts receptor tyrosine kinase signaling in tumor cells. 1848 64

Somatic mutations of LKB1 tumour suppressor gene have been detected in human cancers including non-small cell lung cancer (NSCLC). The relationship between LKB1 mutations and clinicopathological characteristics and other common oncogene mutations in NSCLC is inadequately described. In this study we evaluated tumour specimens from 310 patients with NSCLC including those with adenocarcinoma, adenosquamous carcinoma, and squamous cell carcinoma histologies. Tumours were obtained from patients of US (n=143) and Korean (n=167) origin and screened for LKB1, KRAS, BRAF, and EGFR mutations using RT-PCR-based SURVEYOR-WAVE method followed by Sanger sequencing. We detected mutations in the LKB1 gene in 34 tumours (11%). LKB1 mutation frequency was higher in NSCLC tumours of US origin (17%) compared with 5% in NSCLCs of Korean origin (P=0.001). They tended to occur more commonly in adenocarcinomas (13%) than in squamous cell carcinomas (5%) (P=0.066). LKB1 mutations associated with smoking history (P=0.007) and KRAS mutations (P=0.042) were almost mutually exclusive with EGFR mutations (P=0.002). The outcome of stages I and II NSCLC patients treated with surgery alone did not significantly differ based on LKB1 mutation status. Our study provides clinical and molecular characteristics of NSCLC, which harbour LKB1 mutations.
 ...
PMID:Mutations in the LKB1 tumour suppressor are frequently detected in tumours from Caucasian but not Asian lung cancer patients. 1859 28

BRAF mutations in lung adenocarcinoma are much less common than the more frequently reported and mutually exclusive mutations of KRAS and EGFR genes, and the clinical and histologic phenotype of BRAF adenocarcinomas has not been described. We analyzed 222 adenocarcinomas of lung lacking KRAS and EGFR mutations and identified 10 adenocarcinomas with BRAF-V600E mutation. All BRAF-V600E mutations were heterozygous. There was a slight female predilection (6:4) in these elderly patients (average age 67 y) who were found to have a greater than expected incidence of intralobar satellite nodules and N2 node involvement. The adenocarcinomas were largely of mixed type with a high incidence of papillary (80%) and lepidic growth (50%). Adenocarcinomas with this clinicopathologic phenotype may be worthwhile investigating for BRAF-V600E mutation as more genetically oriented drug therapies emerge.
 ...
PMID:The histopathology of BRAF-V600E-mutated lung adenocarcinoma. 1863 14

Oncogenic KRAS mutations are associated with resistance to anti-EGFR therapy in colorectal carcinoma. Since anti-EGFR monoclonal antibodies are employed in clinical practice in advanced colorectal cancer, KRAS mutations have become an important predictor of therapy outcome. Mutational analysis of KRAS was performed on 163 adenocarcinoma samples. Exons 1-3 of KRAS were analyzed using SSCP and sequencing. Fifty seven (35%) carcinomas had missense point mutations in one of codons 12, 13, 59, 61, 117. In accordance with the published data, missense mutations in codons 12 (66%) and 13 (22%) were the most frequent. Mutations in codons 59 and 117 occurred with the same frequency as in codon 61. The only detected insertion occurred in exon 2. 15-bp insertion resulted in tandem duplication of codons 62-66. Presumably, 5 additional amino acids affected switch II conformation and sustained Ras activity due to decreased GTP hydrolysis. We report this unusual new type mutation.
 ...
PMID:KRAS mutation profile in colorectal carcinoma and novel mutation--internal tandem duplication in KRAS. 1866 74

Soluble isoforms of the epidermal growth factor receptor (sEGFR) previously have been identified in the conditioned culture media (CCM) of the vulvar adenocarcinoma cell line, A431 and within exosomes of the keratinocyte cell line HaCaT. Here, we report that the extracellular domain (ECD) of EGFR is shed from the cell surface of human carcinoma cell lines that express 7x10(5) receptors/cell or more. We purified this proteolytic isoform of EGFR (PI-sEGFR) from the CCM of MDA-MB-468 breast cancer cells. The amino acid sequence of PI-sEGFR was determined by reverse-phase HPLC nano-electrospray tandem mass spectrometry of peptides generated by trypsin, chymotrypsin or GluC digestion. The PI-sEGFR protein is identical in amino acid sequence to the EGFR ECD. The release of PI-sEGFR from MDA-MB-468 cells is enhanced by phorbol 12-myristate 13-acetate, heat-inactivated fetal bovine serum, pervanadate, and EGFR ligands (i.e., EGF and TGF-alpha). In addition, 4-aminophenylmercuric acetate, an activator of metalloproteases, increased PI-sEGFR levels in the CCM of MDA-MB-468 cells. Inhibitors of metalloproteases decreased the constitutive shedding of EGFR while the PMA-induced shedding was inhibited by metalloprotease inhibitors, by the two serine protease inhibitors leupeptin and 3,4-dichloroisocoumarin (DCI), and by the aspartyl inhibitor pepstatin. These results suggest that PI-sEGFR arises by proteolytic cleavage of EGFR via a mechanism that is regulated by both PKC- and phosphorylation-dependent pathways. Our results further suggest that when proteolytic shedding of EGFR does occur, it is correlated with a highly malignant phenotype.
 ...
PMID:Shedding of epidermal growth factor receptor is a regulated process that occurs with overexpression in malignant cells. 1868 26


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>