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: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review highlights the numerous molecular biology findings in the field of lung cancer with potential therapeutic impact in both the near and distant future. At least six lines of research have recently emerged as potential contributors to changes in clinical practice. Abundant pre-clinical and clinical data indicate that BRCA1 mRNA expression is a differential modulator of chemotherapy sensitivity. Low levels predict cisplatin sensitivity and antimicrotubule drug resistance, and the opposite occurs with high levels. Secondly, single nucleotide polymorphisms in the ERCC1 gene influence survival and toxicity with cisplatin-based chemotherapy. The main core of recent research has centered on EGFR mutations and gene copy numbers. For the first time, EGFR mutations have been shown to predict dramatic responses in metastatic lung adenocarcinomas, with a threefold increase in time to progression and survival in patients receiving EGFR tyrosine kinase inhibitors. In contrast, K-ras mutations confer a negative effect in these patients. Evidence has also been accumulated on the crosstalk between estrogen and EGFR receptor pathways, paving the way for clinical trials of EGFR tyrosine kinase inhibitors plus aromatase inhibitors. microRNAs control the expression of cognate target genes, and downregulation of Dicer has been shown to be a strong predictor of relapse in surgically resected non-small-cell lung cancer patients. Finally, overexpression of the Wingless-type (Wnt) genes and methylation of Wnt antagonists like WIF and secreted frizzled related proteins have been documented in non-small-cell lung cancer and are believed to be an important mechanism of cancer stem cell maintenance.
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PMID:Usefulness of predictive tests for cancer treatment. 1693 74

Breast cancer is the second-leading cause of death among Mexican women >35 years of age. At the molecular level, changes in many genetic pathways have been reported to be associated with this neoplasm. To analyze these changes, we determined gene expression profiles and chromosomal structural alterations in tumors from Mexican women. We obtained mRNA to identify expression profiles with microarray technology, and DNA to determine amplifications and deletions, in 10 fresh sporadic breast tumor biopsies without treatment, as well as in 10 nonaffected breast tissues. Expression profiles were compared with genetic changes observed by comparative genomic hybridization (CGH). We compared the expression profiles against the structural alterations from the studied genes by means of microarrays; at least 17 of these genes correlated with DNA copy number alterations. We found that the following genes were overexpressed: LAMC1, PCTK3, CCNC, CCND1, FGF3, PCTK2, L1CAM, BGN, and PLXNB3 (alias PLEXR). Underexpressed genes included CASP9, FGR, TP73, HSPG2, and ERCC1; genes turned off included FRAP1, EPHA2 (previously ECK), IL12A, E2F5, TNFRSF10B, TNFRSF10A, EFNB3, and BCL2. The results will allow us, in the near future, to outline genes that could serve as diagnostic, prognostic, or target therapy markers for the Mexican population.
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PMID:Genetic expression profiles and chromosomal alterations in sporadic breast cancer in Mexican women. 1701 86

Analysis of the combined effects of polymorphisms in genes encoding xenobiotic metabolizing enzymes (XMEs) and DNA repair proteins may be a key to understanding the role of these genes in the susceptibility of individuals to mutagens. In the present study, we performed an in vitro experiment on lymphocytes from 118 healthy donors that measured the frequency of diepoxybutane (DEB) induced sister chromatid exchanges (SCEs) in relation to genetic polymorphisms in genes coding for XMEs (CYP1A1, CYP2E1, GSTT1, EPHX, and NAT2), as well as DNA repair proteins (XRCC1, XRCC2, XRCC3, XPD, XPA, XPC, XPG, XPF, ERCC1, BRCA1, NBS1, and RAD51). We found that GSTT1(-) and CYP2E1 c1/c2 polymorphisms were associated with higher DEB-induced SCE frequencies, and that NAT2 G(590)A was associated with lower SCE induction by DEB. Analysis of the effect of pairs of genes showed that for a fixed GSTT1 genotype, the SCE level increased with an increasing number of Tyr alleles in EPHX codon 113. We found that among GSTT1(+) individuals the DEB-induced SCE level was significantly lower when the EPHX 139 codon was His/Arg rather than His/His. An interaction between polymorphisms in CYP2E1 and at EPHX codon 113 was also observed. The results of our study confirm observations in cancer patients and in people exposed to xenobiotics indicating that sensitivity to mutagens depends upon a combined effect of a variety of "minor impact" genes. Moreover, our results indicate that polymorphisms in genes coding for XMEs have a greater influence on the genotoxic activity of DEB, measured by DEB-induced SCE frequency, than polymorphisms in genes encoding DNA repair proteins.
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PMID:Influence of polymorphisms in xenobiotic-metabolizing genes and DNA-repair genes on diepoxybutane-induced SCE frequency. 1707 1

Current choice of cancer therapy is usually empirical and relies mainly on the statistical prediction of the treatment success. Molecular research provides some opportunities to personalize antitumor treatment. For example, life-threatening toxic reactions can be avoided by the identification of subjects, who carry susceptible genotypes of drug-metabolizing genes (e.g. TPMT, UGT1A1, MTHFR, DPYD). Tumor sensitivity can be predicted by molecular portraying of targets and other molecules associated with drug response. Tailoring of antiestrogen and trastuzumab therapy based on hormone and HER2 receptor status has already become a classical example of customized medicine. Other predictive markers have been identified both for cytotoxic and for targeted therapies, and include, for example, expression of TS, TP, DPD, OPRT, ERCC1, MGMT, TOP2A, class III beta-tubulin molecules as well as genomic alterations of EGFR, KIT, ABL oncogenes.
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PMID:Molecular-based choice of cancer therapy: realities and expectations. 1730 83

Chromosomal aberrations (CAs) are important genetic alterations in the development and progression of the majority of human cancers. The frequency with which such alterations occur depends to a large extent on polymorphisms of DNA-repair genes and in genes coding for xenobiotic metabolizing enzymes, which are involved in the processes of activation and inactivation of xenobiotics. The frequency of bleomycin (BLM)-induced CAs is an indirect measure of the effectiveness of DNA repair mechanisms, and a predictor of environment-related risk of cancer. Our study was conducted on the human peripheral blood lymphocytes of 82 healthy volunteers. The aim of the study was to elucidate whether the frequency of BLM-induced CAs is correlated with polymorphisms of selected genes involved in different mechanisms of DNA repair such as: XRCC1 [base excision repair]; XPA, XPC, XPG, XPD, XPF, ERCC1 [nucleotide excision repair], NBS1, RAD51, XRCC2, XRCC3, RAD51, and BRCA1 [homologous recombination], as well as in genes encoding xenobiotic metabolizing enzymes, such as CYP1A, CYP2E1, NAT2, GSTT1, and EPHX (mEH). Our study indicated that, of the polymorphisms studied, only XPC (exon 15 and intron 11) is associated with BLM-induced CAs, suggesting a role of the NER pathway in the repair of BLM-induced chromosomal aberrations.
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PMID:Polymorphism in nucleotide excision repair gene XPC correlates with bleomycin-induced chromosomal aberrations. 1768 59

Recent years have brought tremendous progress in the development of genomic and proteomic platforms to study cancer biology. Tests based on these platforms are helpful in early diagnosis, prognosis, and prediction of treatment benefit. Molecular studies performed on minimally invasive material (plasma, sputum) from individuals participating in longitudinal or case-control studies have approximately 70%-90% sensitivity and specificity to detect lung cancer. In operable non-small-cell lung cancer, genomic and proteomic studies yield better prognostic information than pathologic staging. There are several examples of successful identification of predictive assays for benefit from chemotherapy (ERCC1, RRM1, p27Kip1, and p53 expression) or targeted therapies (epidermal growth factor receptor [EGFR] gene copy number, EGFR activating mutations, EGFR protein expression, serum proteomic profile). These markers should be prospectively tested in clinical studies before they can be routinely used in the clinic.
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PMID:Advances in genomic and proteomic studies of non-small-cell lung cancer: clinical and translational research perspective. 1850 Oct 93

Myelodysplastic syndrome (MDS) represents a good model for research of prognostic/progression markers due to frequent transformation into acute myeloid leukemia (AML). We analysed expression profiles of 26 MDS and 6 AML patients using cDNA arrays comprising 588 gene probes. The array data were validated in a larger set of 46 patients by qRT-PCR. Data analysis identified differently expressed genes in MDS and the cluster of four genes (ERCC1, FLT1, NME4 and PCNA) whose expression was correlated with MDS subtypes. High expression of these genes was associated with poor prognosis and/or unfavorable outcome. Furthermore, PCNA expression was correlated with peripheral blood blast percentage (r = 0.71, p < 0.05), while the other genes showed non-significant correlation. Our findings demonstrate the progressive up-regulation of the genes along the sequence of 5q-syndrome/RCMD/RAEB/de novo AML, suggesting their association with disease progression.
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PMID:High expression of ERCC1, FLT1, NME4 and PCNA associated with poor prognosis and advanced stages in myelodysplastic syndrome. 1860 18

Inherent to most tissue image analysis routines are user-defined steps whereby specific pixel intensity thresholds must be set manually to differentiate background from signal-specific pixels within multiple images. To reduce operator time, remove operator-to-operator variability, and to obtain objective and optimal pixel separation for each image, we have developed an unsupervised pixel-based clustering algorithm allowing for the objective and unsupervised differentiation of signal from background, and differentiation of compartment-specific pixels on an image-by-image basis. We used the Automated QUantitative Analysis (AQUA) platform, a well-established automated fluorescence-based immunohistochemistry image analysis platform used for quantification of protein expression in specific cellular compartments to demonstrate utility of this methodology. As a metric for cellular compartmentalization, we examined correlation of percentage nuclear volume with histologic grade in 3 serial sections of a large cohort (n=669) of invasive breast cancer samples. We observed a significant (P=0.002, 0.006, and 0.08) difference in mean percentage nuclear volume between low and high-grade tumors. Reproducibility of percentage nuclear volume was also significant (P<0.001) across 3 serial sections. We then quantified compartment-specific expression of 5 biomarkers in 3 cancer types for association with outcome: estrogen receptor (nuclear), progesterone receptor (nuclear), HER2 (membrane/cytoplasm), ERCC1 (nuclear), and PTEN (cytoplasm). All 5 markers showed an expected and significant (P<0.05) association with survival. This new clustering algorithm thus produces accurate and precise compartmentalization for assessment of target gene expression, and will enhance the efficiency and objectivity of the current Automated QUantitative Analysis and other image analysis platform.
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PMID:Development of an unsupervised pixel-based clustering algorithm for compartmentalization of immunohistochemical expression using Automated QUantitative Analysis. 1931 15

An impressive number of publications refer to prognostic and predictive factors in lung cancer. TNM classification and performance status significantly influence the choice of treatment and strongly predict patients' survival. Depending on the population studied (small cell or non-small cell cancer, operable or not) other independent factors improve the prediction of prognosis; they are clinical, biological, radiological or molecular and pertain to the tumor or the patient. Molecular targeted therapies development has renewed the interest towards predictive factors. New strategies are developed to explore individual response to treatment such as EGFR tyrosine-kinase inhibitors, without success for anti-angiogenic treatments. Conventional cytotoxic agents may also be customized with predictive factors (i.e. ERCC1 or RRM1). Large multicenter studies are needed to validate new independent prognostic factors and increase our current knowledge aiming at separating patients who will really benefit from therapies of those who will only experience the side effects.
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PMID:[Prognostic and predictive factors in lung cancer]. 1935 14

Recurrence after neoadjuvant chemo-radiotherapy (CRT) followed by surgery is high in patients with esophageal cancer. No standard second line therapy is currently available for patients with recurrence. This study aimed to evaluate the expression of chemo-radiosensitive genes after neoadjuvant CRT in residual tumor cells. Thirteen patients with esophageal squamous cell carcinoma underwent 5-fluorouracil (5-FU) and cisplatin (CDDP) based CRT followed by surgery. Total RNA was successfully obtained from 6 formalin-fixed paraffin-embedded (FFPE) specimens using proteinase K digestion and phenol chloroform extraction. TS and DPD as the 5-FU pathway gene, ERCC1 as the CDDP pathway gene, and EGFR, VEGF, HIF1a as radioresistant genes were measured using real-time reverse transcription polymerase chain reaction; comparing the mRNA level of each gene in pre-CRT biopsy with that in post-CRT FFPE specimens. Five patients had less than one-third residual tumor cells in resected specimens histopathologically; eight had more than two-thirds residual tumor cells. There were significant increases in TS (p=0.02) and DPD (p=0.01) levels in residual tumor cells after CRT. Significant decreases in ERCC1 (p=0.03), EGFR (p=0.01), VEGF (p=0.003) and HIF1a (p=0.003) levels were observed. 5-FU and CDDP based CRT up-regulated 5-FU pathway genes and down-regulated CDDP pathway and radioresistant genes. The expression of chemo-radiosensitive genes was significantly changed in residual tumor cells after CRT. Gene expression analysis of residual tumor cells in FFPE specimens may be useful when selecting a second line chemotherapy regimen for recurrent esophageal cancer after CRT.
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PMID:Clinical significance of the gene expression profile in residual tumor cells after neoadjuvant chemo-radiotherapy for esophageal cancer. 1942 28


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