Amplification of the MDM2 gene, but not expression of splice variants of MDM2 mRNA, is associated with prognosis in soft tissue sarcoma

The MDM2 gene encodes a 90-kDa oncoprotein that is overexpressed in several human carcinomas, osteosarcomas, gliomas and soft tissue sarcomas (STSs), This overexpression is the result of several mechanisms, for example, enhan ced transcription or translation, gene amplification and alternative splici ng. We found that IP of 67 (28.4%) STS specimens contained an amplified MDM 2 gene, The amplification was more likely to be present in grade 1 tumors t han in grade 2 or 3 tumors (58% of grade 1 tumors vs. 15% of grade 2 or 3 t umors, p = 0,001, chi (2) test). Furthermore, patients with tumors that con tained an amplified MDM2 gene had a survival estimate (87 months) that was longer than that of patients with tumors that lacked an amplified gene (40 months; p = 0.02, log-rank test), Alternatively and aberrantly spliced MDM2 mRNAs were detected in human STSs by a highly sensitive reverse transcript ion-polymerase chain reaction method. Of 71 tumor samples, 38 (54%) showed evidence of the spliced forms. which included MDM2-A, MDM2-B and several va riants exclusively expressed in STSs, A common feature of all forms was the absence of the MDM2 N-terminal region. which includes the TP53-binding reg ion. Furthermore, the presence of the spliced forms was associated with ele vated levels of TP53 (P = 0.01, chi (2) test). Although the presence of spl iced forms was associated with late-stage tumor phenotypes (p = 0.05, chi ( 2) test), we observed no relationship between the presence of splice varian ts and patient outcome. (C) 2001 Wiley-Liss, Inc.