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)

Recent data have suggested considerable molecular differences in cancers from various ethnical groups. As molecular features are increasingly used for predicting cancer prognosis and response to therapy, better knowledge of ethnic molecular features is important. To identify potential molecular differences between breast cancers in Europe and the Middle East, we analyzed consecutive breast cancer series from Switzerland (n=2197) and Saudi Arabia (n=204). Tissue microarrays were analyzed by fluorescence in situ hybridization for HER2, CCND1, MYC, and EGFR amplification. The data revealed marked differences between Saudi and Swiss patients. Saudi breast cancers had a markedly higher frequency of HER2 (31 vs 17%; P<0.0001) and MYC (16 vs 5%; P<0.0001) amplifications than Swiss breast cancers. Remarkably, this was partly due to a much higher incidence of grade 3 cancers in the Saudi than in the Swiss population (65 vs 32%; P<0.0001). However, differences in amplification frequency hold also true within grade 3 cancers (HER2: 40 vs 30%, P<0.05; MYC: 22 vs 11%, P=0.002). Interestingly, in combination with known age standardized incidence rates of breast cancer in Saudi Arabia (21.6/100 000) and Switzerland (70.1/100 000), these data suggest that the incidence of high-grade breast cancer is comparable for Saudi and Swiss women, while the incidence of low-grade breast cancers is about 14 times lower in Saudi than for Swiss women. These observations suggest that a difference in genetic susceptibility and/or lifestyle between Saudi and Swiss women has a substantial and much higher than expected impact on the risk of low-grade breast cancer.
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PMID:Predominance of high-grade pathway in breast cancer development of Middle East women. 1580 83

Here we report the complex pattern of genomic imbalances and rearrangements in a panel of 19 renal cell carcinoma cell lines detected with molecular cytogenetic analysis. Consistent heterogeneity in chromosome number was found, and most cell lines showed a near-triploid chromosome complement. Several cell lines showed deletions of the TP53 (alias p53), CDKN2A (alias p16), and VHL genes. Multiplex fluorescence in situ hybridization (M-FISH) analysis revealed chromosome 3 translocated to several other partners chromosomes, as well as breakage events commonly affecting chromosomes 1, 5, 8, 10, and 17. The most common abnormality detected with comparative genomic hybridization (CGH) was deletions of chromosome 3p, with loss of the RASSF1, FHIT, and p44S10 loci frequently involved. CGH gain of 5q showed overrepresentation of the EGR1 and CSF1R genes. Recurrent alterations to chromosome 7 included rearrangement of 7q11 and gains of the EGFR, TIF1, and RFC2 genes. Several lines exhibited rearrangement of 12q11 approximately q14 and overrepresentation of CDK4 and SAS loci. M-FISH revealed several other recurrent translocations, and CGH findings included loss of 9p, 14q, and 18q and gain of 8q, 12, and 20. Further genomic microarray changes included loss of MTAP, IGH@, HTR1B, and SMAD4 (previously MADH4) and gains of MYC and TOP1. An excellent correlation was observed between the genomic array and FISH data, demonstrating that this technique is effective and accurate. The aberrations detected here may reflect important pathways in renal cancer pathogenesis.
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PMID:A combination of molecular cytogenetic analyses reveals complex genetic alterations in conventional renal cell carcinoma. 1586 Mar 50

Therapy-related myeloid leukemia (t-AML) is a distinctive clinical syndrome occurring after exposure to chemotherapy (CT) or radiotherapy (RT). We studied 306 consecutive patients referred to the University of Chicago with cytogenetic analyses. Since 1972, 141 males and 165 females with a median age of 51 years (range: 3-83 years) at primary diagnosis and 58 years (range: 6-86 years) at secondary diagnosis were analyzed. Patients had received various cytotoxic agents including alkylating agents (240 patients, 78%) and topoisomerase II inhibitors (115 patients, 39%). One hundred and twenty-one (40%) had received CT alone, 43 (14%) had received RT alone, and 139 (45%) had received both modalities. At diagnosis of t-AML, 282 (92%) had clonal abnormalities involving chromosome 5 (n=63), chromosome 7 (n=85), both chromosomes 5 and 7 (n=66), recurring balanced rearrangements (n=31), or other clonal abnormalities (n=39); 24 had a normal karyotype. Abnormalities of chromosomes 5 and/or 7 accounted for 76% of all cases with an abnormal karyotype. Seventeen patients had developed t-AML after autologous stem cell transplantation, but no unique pattern of cytogenetic abnormalities was observed. Patients presenting with acute leukemia were more likely to have a balanced rearrangement than those presenting with myelodysplasia (28% versus 4%, p<0.0001). Shorter latency was observed for patients with balanced rearrangements (median: 28 months versus 67 months; p<0.0001). Median survival after diagnosis of t-AML was 8 months; survival at 5 years was less than 10%. To gain insights into the molecular basis of this disease, we performed gene expression profiling of CD34+ hematopoietic progenitor cells from t-AML patients. We found distinct subtypes of t-AML that have characteristic gene expression patterns. Common to each of the subgroups are gene expression patterns typical of arrested differentiation in early progenitor cells. Leukemias with a -5/del(5q) have a higher expression of genes involved in cell cycle control (CCNA2, CCNE2, CDC2), checkpoints (BUB1), or growth (MYC), and loss of expression of the gene encoding interferon consensus sequence-binding protein (ICSBP). A second subgroup of t-AML is characterized by down-regulation of transcription factors involved in early hematopoiesis (TAL1, GATA1, and EKLF) and overexpression of proteins involved in signaling pathways in myeloid cells (FLT3) and cell survival (BCL2). Establishing the molecular pathways involved in t-AML may facilitate the identification of selectively expressed genes that can be exploited for the development of targeted therapies.
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PMID:Therapy-related myeloid leukaemia: a model for leukemogenesis in humans. 1593 16

Fluorescence in situ hybridization analysis for evaluation of 7, 8, X chromosomes and EGFR, LPL, MYC, AR genes in 79 neoplastic foci from 56 patients with clinically localized prostate cancer was performed. We found aneusomy for chromosome 7, 8 and X in 74/77 (96.1%), 56/76 (73.7%), 26/70 (37.1%) of examined foci respectively. No specimen was amplified for EGFR and AR genes, only 2/71 (2.8%) specimens showed MYC gene amplified. LPL deletion was present in 52/76 (68.4%) specimens. Statistically association between Gleason score and both chromosome 7 aneusomy and 8p21 deletion was present. The frequency of chromosome 7 aneusomy was statistically higher in T3-4 cases than T2c and T2a-T2b ones. We considered as unfavorable a genetic set if aneusomy for at least two chromosomes and one altered gene were present. The percentage of tumors, with unfavorable genetic pattern, increased from 36.4 to 75.0% in those with Gleason >7 and from 40.0 to 73.7% in those with stage T3 or more. These alterations could be considered potent genetic markers adjunctive to conventional prognostic parameters. Our objective was to establish specific genetic profiles which may discriminate favorable and unfavorable genetic prognosis tumors.
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PMID:Cytogenetic profiles as additional markers to pathological features in clinically localized prostate carcinoma. 1600 7

There appear to be two pathways involved in the pathogenesis of premalignant non-immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Nearly half of tumors are nonhyperdiploid, and mostly have one of five recurrent IgH translocations: 16% 11q13 (CCN D1), 3% 6p21 (CCN D3), 5% 16q23 (MAF), 2% 20q12 (MAFB), and 15% 4p16 (FGFR3 and MMSET). The remaining hyperdiploid tumors have multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21, and infrequently one of these five translocations. Although cyclin D1 is not expressed by healthy lymphoid cells, it is bi-allelically dysregulated in a majority of hyperdiploid tumors. Virtually all MM and MGUS tumors have dysregulated and/or increased expression of cyclin D1, D2, or D3, providing an apparent early, unifying event in pathogenesis. The patterns of translocations and cyclin D expression (TC) define a novel classification that includes eight groups: 11q; 6p; MAF; 4p; D1 (34%); D1+D2 (6%); D2 (17%); and none (2%). The hyperdiploid D1 group is virtually absent in extramedullary MM and MM cell lines, suggesting a particularly strong dependence on interaction with the bone marrow microenvironment. Despite shared progression events (RAS mutations, MYC dysregulation, p53 mutations, and additional disruption of the retinoblastoma pathway), the phenotypes of MGUS and MM tumors in the eight TC groups is determined mainly by early oncogenic events. Similar to acute lymphocytic leukemia, MM seems to include several diseases (groups) that have differences in early or initiating events, global gene expression patterns, bone marrow dependence, clinical features, prognosis, and response to therapy.
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PMID:Molecular pathogenesis and a consequent classification of multiple myeloma. 1615 16

Quantitative and structural genetic alterations cause the development and progression of prostate cancer. A number of genes have been implicated in prostate cancer by genetic alterations and functional consequences of the genetic alterations. These include the ELAC2 (HPC2), MSR1, and RNASEL (HPC1) genes that have germline mutations in familial prostate cancer; AR, ATBF1, EPHB2 (ERK), KLF6, mitochondria DNA, p53, PTEN, and RAS that have somatic mutations in sporadic prostate cancer; AR, BRCA1, BRCA2, CHEK2 (RAD53), CYP17, CYP1B1, CYP3A4, GSTM1, GSTP1, GSTT1, PON1, SRD5A2, and VDR that have germline genetic variants associated with either hereditary and/or sporadic prostate cancer; and ANXA7 (ANX7), KLF5, NKX3-1 (NKX3.1), CDKN1B (p27), and MYC that have genomic copy number changes affecting gene function. More genes relevant to prostate cancer remain to be identified in each of these gene groups. For the genes that have been identified, most need additional genetic, functional, and/or biochemical examination. Identification and characterization of these genes will be a key step for improving the detection and treatment of prostate cancer.
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PMID:Prevalent mutations in prostate cancer. 1626 36

Tissue microarrays (TMAs) are potentially suited to find associations between molecular features and clinical outcome. Enhanced cell proliferation, as measured by Ki67 immunohistochemistry, is related to poor patient prognosis in many different tumor types. Ki67 expression shows considerable intratumoral heterogeneity. It is unclear if the TMA format is suitable for the analysis of potentially heterogeneous markers because of the small size of TMA spots. We have analyzed a breast cancer TMA containing 2,517 breast tissues, including 2,222 neoplastic and 295 normal or premalignant samples, for Ki67 labeling index (Ki67 LI) and additional markers with a known relationship to Ki67 LI by immunohistochemistry (ER, PR, Bcl-2, Egfr, p16, p53) and Fluorescence in situ hybridization (HER2, MDM2, CCND1, MYC). A high Ki67 LI was linked to tumor phenotype including grade (p < 0.0001), stage (p < 0.0001), nodal stage (p = 0.0018), and patient prognosis (p < 0.0001), elevated protein levels of p53, p16 and Egfr, reduced levels of Bcl2, ER, and PR (p < 0.0001 each), as well as amplifications of HER2, MYC, CCND1 and MDM2 (p < 0.0001 each). In summary, all expected associations between Ki67 and the analyzed molecular markers could be reproduced with high statistical significance using a TMA containing only one tissue sample per tumor, measuring 0.6 mm in diameter. We conclude that associations with cell proliferation can be reliably analyzed in a TMA format.
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PMID:Tissue microarrays for comparing molecular features with proliferation activity in breast cancer. 1633 4

Individuals with Down syndrome (DS) are predisposed to develop acute megakaryoblastic leukemia (AMKL), characterized by expression of truncated GATA1 transcription factor protein (GATA1s) due to somatic mutation. The treatment outcome for DS-AMKL is more favorable than for AMKL in non-DS patients. To gain insight into gene expression differences in AMKL, we compared 24 DS and 39 non-DS AMKL samples. We found that non-DS-AMKL samples cluster in two groups, characterized by differences in expression of HOX/TALE family members. Both of these groups are distinct from DS-AMKL, independent of chromosome 21 gene expression. To explore alterations of the GATA1 transcriptome, we used cross-species comparison with genes regulated by GATA1 expression in murine erythroid precursors. Genes repressed after GATA1 induction in the murine system, most notably GATA-2, MYC, and KIT, show increased expression in DS-AMKL, suggesting that GATA1s fail to repress this class of genes. Only a subset of genes that are up-regulated upon GATA1 induction in the murine system show increased expression in DS-AMKL, including GATA1 and BACH1, a probable negative regulator of megakaryocytic differentiation located on chromosome 21. Surprisingly, expression of the chromosome 21 gene RUNX1, a known regulator of megakaryopoiesis, was not elevated in DS-AMKL. Our results identify relevant signatures for distinct AMKL entities and provide insight into gene expression changes associated with these related leukemias.
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PMID:Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. 1649 68

Human leukemia-derived cell lines containing characteristic chromosomal translocations and inversions have been instrumental in identifying fusion genes implicated in the pathogenesis of the corresponding leukemia. Although chimeric fusion genes usually provide early and essential steps in the development of leukemia, they are not in themselves sufficient, requiring additional genetic events. The nature of these secondary, cooperating genetic events is not known. The advent of genome wide microarray-based methods for assessing copy number changes made it possible to search for cytogenetically invisible regions of chromosome imbalance. We used BAC microarrays with a resolution of 1 Mb to determine whether cryptic regions of deletion or gain were associated with specific leukemia-associated fusion genes in a series of cell lines. To complement the array analysis, we also applied 24-color karyotyping by M-FISH. This revealed cryptic chromosomal translocations and regions of loss or gain in all the cell lines studied. The chromosomal origin of previously unidentified marker chromosomes was revealed. In all cases, chromosomes described as monosomic were shown to be involved in unbalanced translocations with concurrent loss and/or gain of chromosomal material. The extent of these amplified and deleted regions was more accurately defined. Finally, small regions of deletion and amplification, often including genes known to be involved in leukemia progression (for example MYC, TP53, CDKN2A, and KIT), were identified.
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PMID:Array CGH of fusion gene-positive leukemia-derived cell lines reveals cryptic regions of genomic gain and loss. 1652 83

Adenocarcinomas of the gastroesophageal junction (GEJ) show frequent high-level amplifications (HLA), but the underlying genes are not well defined. We have characterized genomic gain in 14 GEJ carcinomas by array-based comparative genomic hybridization (aCGH). The most frequent gains and amplifications were detected at 7q (57%), 8q (57%), 17q (64%), and 20q (79%), with minimally amplified regions at 7q21.1, 8q24.2, 17q12, and 20q13.2. Five HLA were detected on 7q, one on 8q, two on 17q, and three on 20q. HLA of 8q24 and 17q12 were related to MYC and ERBB2, respectively. The HLA on 7q21 was associated recurrently with ABCB1, whereas the amplified region on 20q13 implicated ZNF217, BCAS1, and CYP24. RNA expression analysis of 11 adenocarcinomas by reverse-transcription polymerase chain reaction was performed for cancer-related genes residing at 7q21 (ABCB1, ABCB4, CDK6, HGF, DMTF1, SRI, TP53AP1) and 20q13 (ZNF217, BCAS1, CYP24, TNFRSF6B). The most frequently upregulated gene on 7q21 was HGF (45%), but there was no association with genomic amplification. The most frequently overexpressed gene at 20q13 was BCAS1 (27%), which was related to HLA of this region (P = 0.006) in all three cases. We conclude that HLA occur often in GEJ adenocarcinomas. The gene responsible for the HLA of 7q21 requires further investigation, whereas BCAS1 is a good candidate for the frequent amplification of 20q13.
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PMID:Genomic array and expression analysis of frequent high-level amplifications in adenocarcinomas of the gastro-esophageal junction. 1663 73


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