THE PROTOONCOGENE CHOP GADD153, INVOLVED IN GROWTH ARREST AND DNA-DAMAGE RESPONSE, IS AMPLIFIED IN A SUBSET OF HUMAN SARCOMAS

The C/EBP-homologous transcription factor CHOP (GADD153) is inducible by growth inhibition or DNA damage, and has been shown to be oncogenically activated by the specific (12;16) translocation in human myxoid liposarcoma. We have now found CHOP amplification in two sarcoma cell lines with previously reported amplification of the nearby GLI gene. Among 98 other human sarcomas of various types, CHOP was amplified in a hemangiopericytoma, a liposarcoma, and two osteosarcomas. High constitutive expression levels of CHOP were observed in tumors with gene amplification, but also in some other samples. The nearby MDM2 gene, which codes for a protein that may inactivate wild-type p53, has previously been reported to be frequently amplified in sarcoma. In our sarcoma panel, MDM2 was amplified in 9 cases. MDM2 and CHOP were co-amplified in two of these, whereas the two osteosarcomas had amplified CHOP but not MDM2. CHOP was amplified in both cell lines with GLI amplification, and MDM2 only in one. No mutations in the TP53 gene have been found in samples with amplification of MDM2. In contrast, the cell line in which CHOP but not MDM2 was amplified had mutated TP53, suggesting that selection of this amplicon was not mediated through p53 inactivation.