[The EWS gene rearrangement in Ewing tumors: key to the disease].
The family of Ewing tumors (ET) is characterised by a unique gene rearrangement which is represented by a translocation t(11;22) (q24;q12) or a deletion del 22q12 in most cytogenetically analysable cases. The recent cloning of the underlying gene fusion provides the basis for the diagnostic detection of minimal amounts of residual tumor cells at resection margins, in blood and bone marrow. In addition, the very first steps in ET tumorigenesis can be studied on a functional basis. In this study, a variety of fusion products were identified with a sensitivity of 10(-6) by means of RT-PCR. In 20 of 22 ET, a gene rearrangement was identified which resulted in the substitution of the effector domain of one of the closely related DNA-binding oncogenes, FLI-1 or ERG, by the transactivating domain of a new gene, EWS. Presumably, the oncogene and consequently its target genes are activated by this type of translocation. If the EWS domain was replaced with a transcriptionally irrelevant domain by transfection of a recombinant gene into ET cells, competition with the endogenous chimeric oncogene-product for DNA-binding was observed resulting in a partial growth inhibition. Activation of FLI-1 has been previously shown to occur as a primary event in Friend virus induced mouse erythroleukemia. During progression of this disease, inactivating p53 mutations have been observed frequently. In contrast, such aberrations were found to be extremely rare in ET.
Childrens Cancer Research Institute (CCRI), St. Anna Kinderspital, Wien.
H
H
Kovar
A
A
Zoubek
C
C
Pfleiderer
G
G
Jug
A
A
Auinger
D
D
Aryee
P F
PF
Ambros
M
M
Salzer-Kuntschik
G
G
Amann
R
R
Windhager
D000293:Adolescent; D001853:Bone Marrow / Q000473:pathology; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11; D002892:Chromosomes, Human, Pair 22; D004268:DNA-Binding Proteins / Q000235:genetics; D051766:Early Growth Response Protein 1; D005260:Female; D015321:Gene Rearrangement / Q000235:genetics*; D006801:Humans; D017874:Immediate-Early Proteins; D008297:Male; D009360:Neoplastic Cells, Circulating; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D014178:Translocation, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; C072312:ERG protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D015682:Retroviridae Proteins, Oncogenic; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D016159:Tumor Suppressor Protein p53
Das EWS-Genrearrangement in Ewing Tumoren: Schlüssel zur Erkrankung.