Significance of HDMX-S (or MDM4) mRNA splice variant overexpression and HDMX gene amplification on primary soft tissue sarcoma prognosis.
The product of the HDMX (or MDM4) gene is structurally related to the MDM2 oncoprotein and is also capable of interacting with the tumor suppressor protein p53. The aim of our study was to determine the amplification status of the HDMX gene and the expression of the HDMX mRNA (particularly that of the HDMX-S splice variant) in soft-tissue sarcomas (STS). Patients with STS were evaluated for the status of HDMX gene amplification (n = 66) and HDMX-S mRNA expression (n = 57) within their tumors. DNA, total RNA and protein were isolated from frozen tumor tissue. We determined that the HDMX-S splice variant transcript was predominant in a subset (14%) of tumor samples and that its expression was correlated with decreased patient survival (15 vs. 53 months, p < 0.0001, log-rank test) and with a 17-fold increased risk of a tumor-related death (p < 0.0001, multivariate Cox's regression model). The tumors from these patients also expressed elevated levels of HDMX-S protein. The HDMX gene was amplified in 17% of STSs, and the gene amplification was associated with poor prognosis (RR = 6.5, p < 0.0001). There was no correlation between the HDMX gene amplification and overexpression of the HDMX-S splice variant. In summary, our data indicate that both the overexpression of the HDMX-S transcript as well as HDMX gene amplification are important prognostic markers for STS.
Bartel
Frank
F
Institute of Pathology, Faculty of Medicine, University of Halle-Wittenberg, Halle/Saale, Germany. frank.bartel@medizin.uni-halle.de
Schulz
Jördis
J
Böhnke
Anja
A
Blümke
Karen
K
Kappler
Matthias
M
Bache
Matthias
M
Schmidt
Hannelore
H
Würl
Peter
P
Taubert
Helge
H
Hauptmann
Steffen
S
D000328:Adult; D017398:Alternative Splicing; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005354:Fibrosarcoma / Q000235:genetics; D005784:Gene Amplification; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008080:Liposarcoma / Q000235:genetics; D008297:Male; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics*; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012509:Sarcoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D017931:DNA Primers; D004273:DNA, Neoplasm; D047908:Intracellular Signaling Peptides and Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm