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)

Preleukemia is thought to be a clonal disorder of hemopoietic stem cells. The conversion of a normal cell into a preleukemic and ultimately leukemic state is a multistep process requiring the accumulation of a number of genetic lesions. The myelodysplastic syndromes have become a paradigm for human preleukemia, where nonrandom chromosomal abnormalities, including complete or partial deletions of chromosomes five and seven, trisomy eight and Y chromosome loss suggest specific changes. Of particular significance are 5q deletions, as many genes important in hemopoiesis are located in this region, including the proto-oncogene FMS, which encodes the receptor for the macrophage colony-stimulating factor, CSF-1. Genetic damage such as point mutations in the RAS and FMS genes has been detected in preleukemia patients. The RAS gene family (N, K and H) encodes membrane-bound G proteins, which, like other proto-oncogenes, are components of the intracellular signal transduction pathways controlling mitogenesis and differentiation. The characterization of such lesions may ultimately identify those patients at greatest risk of leukemic transformation.
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PMID:Genetic lesions in preleukemia. 142 Apr 44

Prenatal diagnosis of chromosomal and biochemical defects is accepted as a routine in high-risk patients. To eliminate the disadvantages of traditional amniocentesis (late diagnosis) and of chorion villus sampling (placentar mosaics, higher fetal loss rate) we evaluated the facts on amniocentesis during the first 12 weeks of pregnancy. 42 samples were analysed. 21 amniotic fluid samples were from pregnancies before the 13th week of gestation, 21 further punctures were performed between the 13th to 15th week and served as comparative figures. Of 21 samples, diagnosis was possible in 16 cases. Four cultures did not show any growth of cells; in one case, amniotic fluid could not be aspirated. In the comparison group chromosomal diagnosis could be done in every case. An average of 12.3 ml of amniotic fluid were taken. Chromosomal disorders found, included a translocation in chromosome 13/14 as well as a trisomy of chromosome 18. Biochemical defects such as Gaucher's disease and Niemann-Pick disease were excluded. 30 pregnancies without pathological symptoms were seen (mean birth weight 3200 g, mean duration of pregnancy 39 weeks). One case of abortion following amniocentesis was found in the 16th week of gestation. One case of premature delivery occurred in the 34th week and the pregnancy of a 40-year old women was complicated by EPH gestosis while 9 pregnancies were terminated by interruption following the patients' wish. Because chromosomal diagnosis could not be performed in five of 21 cases, amniocentesis during the 13th week of gestation cannot be recommended as a routine method. Early amniocentesis, however, is an alternative to the traditional amniocentesis at the 16th week of gestation.
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PMID:[The diagnostic potential of amniocentesis in the first 12 weeks of pregnancy]. 177 23

DNA-mediated transfer of colchicine-resistance from Djungarian hamster DM5/7 cell line, 750-fold resistant to the drug, was studied. The resistance to colchicine of DM5/7 cells is due to amplification of the genes, possibly coding for the polypeptide p22. Both high-molecular weight DNA (presumably, chromosomal DNA) and low-molecular weight DNA (presumably, extrachromosomal DNA) effectively transferred the colchicine-resistance to Djungarian hamster and mouse cells. DNA of sensitive to colchicine but resistant to ouabain mouse cells CAK-143OuaR was not capable to transfer colchicine-resistance, but effectively transferred ouabain-resistance connected with a mutation in Na+/K+-dependent ATP-ase locus. The differences in genetic transformation with amplified p22 genes and mutant Na+/K+-dependent ATP-ase genes were revealed. All cells of 3 colchicine-resistant transformants of DM-15 cells and all 10 spontaneously derived resistant clones contain the additional chromosome 4. The role of trisomy 4 in the development of colchicine-resistance in DM-15 cells is discussed.
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PMID:[Amplification of portions of the genome in the somatic cells of mammals resistant to colchicine. IV. Genetic transformation using amplified genes from Djungarian hamster cells highly resistant to colchicine]. 668 73

The development of cancer is a multistep process involving accumulation of genetic changes which progressively transform normal cells to neoplastic cells. During the last few years, our understanding and knowledge of the genetic changes involved in ovarian carcinogenesis have increased dramatically. In this review I will focus on karyotypic abnormalities in ovarian cancer and will also refer to molecular studies involving alterations in oncogenes and tumour suppressor genes in ovarian tumorigenesis. Cytogenetic analyses have identified two distinct subgroups. Simple karyotypic changes, trisomy 12 being the most common aberration in this group, are recurrently found in well differentiated ovarian carcinomas. Complex karyotypic abnormalities, including predominantly chromosome losses, deletions and unbalanced translocations, are found in moderately and poorly differentiated carcinomas. The bands and regions most commonly involved in structural rearrangements have been, in decreasing order of frequency, 19p13, 1p36, 1q21, 1q23-25, 3p11-13, 6q21, 19q13, 11p13-15, 11q13, 11q23, 12q24, 12p11-13, and 7p13-22. The finding of identical karyotypic and other genetic changes in tumour samples taken from different sites, such as tumours from both ovaries and omental metastases, indicate that ovarian cancer is of unicentric origin with subsequent metastatic spread giving rise to multiple implants. Molecular genetic changes important in ovarian cancer involve both classes of tumor-associated genes: RAS activation is generally not observed in ovarian cancer. Alterations of MYC1, ERBB2, AKT2, TP53 has been described in some ovarian carcinomas. The temporal relationship of these mutations, i.e. early or late events in ovarian carcinogenesis, remains to be determined.
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PMID:Genetic changes in ovarian cancer. 774 4

Hereditary papillary renal carcinoma (HPRC) is a recently recognized form of inherited kidney cancer characterized by a predisposition to develop multiple, bilateral papillary renal tumours. The pattern of inheritance of HPRC is consistent with autosomal dominant transmission with reduced penetrance. HPRC is histologically and genetically distinct from two other causes of inherited renal carcinoma, von Hippel-Lindau disease (VHL) and the chromosome translocation (3;8). Malignant papillary renal carcinomas are characterized by trisomy of chromosomes 7, 16 and 17, and in men, by loss of the Y chromosome. Inherited and sporadic clear cell renal carcinomas are characterized by inactivation of both copies of the VHL gene by mutation, and/or by hypermethylation. We found that the HPRC gene was located at chromosome 7q31.1-34 in a 27-centimorgan (cM) interval between D7S496 and D7S1837. We identified missense mutations located in the tyrosine kinase domain of the MET gene in the germline of affected members of HPRC families and in a subset of sporadic papillary renal carcinomas. Three mutations in the MET gene are located in codons that are homologous to those in c-kit and RET, proto-oncogenes that are targets of naturally-occurring mutations. The results suggest that missense mutations located in the MET proto-oncogene lead to constitutive activation of the MET protein and papillary renal carcinomas.
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PMID:Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. 914 Mar 97

Comparative genomic hybridization (CGH) was used to detect copy number changes of DNA sequences in the Ewing family of tumours (ET). We analysed 20 samples from 17 patients. Fifteen tumours (75%) showed copy number changes. Gains of DNA sequences were much more frequent than losses, the majority of the gains affecting whole chromosomes or whole chromosome arms. Recurrent findings included copy number increases for chromosomes 8 (seven out of 20 samples; 35%), 1q (five samples; 25%) and 12 (five samples; 25%). The minimal common regions of these gains were the whole chromosomes 8 and 12, and 1q21-22. High-level amplifications affected 8q13-24, 1q and 1q21-22, each once. Southern blot analysis of the specimen with high-level amplification at 1q21-22 showed an amplification of FLG and SPRR3, both mapped to this region. All cases with a gain of chromosome 12 simultaneously showed a gain of chromosome 8. Comparison of CGH findings with cytogenetic analysis of the same tumours and previous cytogenetic reports of ET showed, in general, concordant results. In conclusion, our findings confirm that secondary changes, which may have prognostic significance in ET, are trisomy 8, trisomy 12 and a gain of DNA sequences in 1q.
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PMID:Recurrent gains of 1q, 8 and 12 in the Ewing family of tumours by comparative genomic hybridization. 916 30

Previous karyotyping showed a combined trisomy of chromosome 7 and 17 in sporadic and hereditary papillary renal cell tumours (RCT). A recent molecular analysis revealed a mutation in the MET tyrosine kinase (chromosome 7q31) in the germline of four out of seven families with hereditary papillary RCT (HPRCT). We have analysed germline cells as well as multiple tumours obtained from HPRCT families and sporadic cases for alteration of the MET tyrosine kinase and for allelic duplication at chromosome 7 and 17. We have detected a germ line mutation in the MET tyrosine kinase in one of the two families with HPRCTs and also found the same mutation in the germ line of one patient with clinically recognized multiple, bilateral papillary RCTs but without family history. The mutant MET allele is consequently duplicated and overexpressed in tumour cells indicating that duplication of the mutant MET allele is necessary before cells enter the tumorigenic pathway. The lack of germline mutation in two members of another HPRT family and duplication of the same parental allele of chromosome 7 in multiple tumours suggests that a germ line event other than mutation of MET tyrosine kinase is involved in the development of these tumours. Duplication of different alleles of chromosome 7 in sporadic and of chromosome 17 in both types of tumours excludes a germline mutation at these chromosomal sites.
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PMID:Duplication and overexpression of the mutant allele of the MET proto-oncogene in multiple hereditary papillary renal cell tumours. 971 75

The gene defect for hereditary papillary renal carcinoma (HPRC) has recently been mapped to chromosome 7q, and germline mutations of MET (also known as c-met) at 7q31 have been detected in patients with HPRC (ref. 2). Tumours from these patients commonly show trisomy of chromosome 7 when analysed by cytogenetic studies and comparative genomic hybridization (CGH). However, the relationship between trisomy 7 and MET germline mutations is not clear. We studied 16 renal tumours from two patients with documented germline mutations in exon 16 of MET. Fluorescent in situ hybridization (FISH) analysis showed trisomy 7 in all tumours. To determine whether the chromosome bearing the mutant or wild-type MET gene was duplicated, we performed duplex PCR and phosphoimage densitometry using polymorphic microsatellite markers D7S1801 and D7S1822, which were linked to the disease gene locus, and D1S1646 as an internal control. We determined the parental origin of chromosome alleles by genotyping parental DNA. In all 16 tumours there was an increased signal intensity (2:1 ratio) of the microsatellite allele from the chromosome bearing the mutant MET compared with the allele from the chromosome bearing the wild-type MET. Our study demonstrates a non-random duplication of the chromosome bearing the mutated MET in HPRC and implicates this event in tumorigenesis.
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PMID:Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. 973 34

Congenital mesoblastic nephroma (CMN) is an infantile spindle cell tumor of the kidney that is subdivided into "classical" and "cellular" forms based on the degree of cellularity and mitotic activity. The histogenesis of CMN remains obscure, but relationships to other pediatric renal neoplasms have been proposed. However, cellular CMN is virtually identical histologically to congenital fibrosarcoma (CFS), a malignant tumor of fibroblasts in children of the same age group. Moreover, cytogenetic studies have reported common trisomies in CFS and cellular CMN, particularly of chromosome 11. We show here that t(12;15)(p13;q25)-associated ETV6-NTRK3 gene fusions described in CFS are also present in cellular CMN. ETV6-NTRK3 chimeric transcripts were detected in 8 of 9 cellular CMNs and 2 of 2 mixed CMNs. In contrast, all of the four classical CMNs tested were negative, as were cases of Wilms' tumor and clear cell sarcoma of the kidney. Moreover, we found trisomy 11 only in cellular or mixed CMNs with the ETV6-NTRK3 gene fusion. Our studies indicate that classical and cellular CMN have different genetic features and support the concept that cellular CMN is histogenetically related to CFS. They also provide insight into potential mechanisms involved in the transformation of the classical into the cellular form of CMN.
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PMID:ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. 982 7

The first gene found to be amplified in human glioblastomas was EGFR at 7p12. More recently the MET gene at 7q31 was also reported amplified. We have studied chromosome 7 in a series of 47 glioblastomas by FISH, RFLP and microsatellite analysis. Four per cent (2/47) had 1 centromere, 26% (12/47) 2, 32% (15/47) 3, 4% (2/47) 4, and 34% (16/47) had subpopulations with variable numbers of chromosome 7 centromeres. In 25 of the 47 tumors (53%) the pattern of allelic imbalance observed at each informative locus was similar and in accord with the FISH data, indicating loss or gain of complete chromosome copies. In 32% of tumors (15/47) varying allelic imbalance was seen at different loci along the chromosome indicative of loss or gain of parts of chromosome 7 on a background of disomy, trisomy, tetrasomy, or polysomy. Amplification was studied in an extended series of 121 glioblastomas, and was seen at the 7p12 region in 47 tumors (39%). Forty-two tumors showed amplification of EGFR and 12 of these had extensive amplicons including a number of adjacent loci, always involving only 1 allele. The amplicons of 5 tumors (11%) did not include EGFR, indicating that other unidentified genes in the region are targeted for amplification. Amplification of MET was not found. The findings show that copy number changes of chromosome 7 are common and that a number of genes may be targeted for amplification at 7p12 in glioblastomas.
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PMID:Chromosome 7 rearrangements in glioblastomas; loci adjacent to EGFR are independently amplified. 986 36


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