A comparative study of P53/MDM2 genes alterations and P53/MDM2 proteins immunoreactivity in soft-tissue sarcomas.
In the present study, the expression of P53 and MDM2 proteins were examined in 94 soft-tissue sarcomas (35 malignant fibrohistiocytomas, 15 neurosarcomas, 14 liposarcomas, 13 leiomyosarcomas, 11 fibrosarcomas and 6 dermatofibrosarcomas) by immunohistochemistry. The immunohistochemical findings were correlated with P53 mutation analysis using PCR-SSCP, PCR-HDF and direct sequencing, and MDM2 amplification studies by differential PCR. P53 immunopositivity was found in 25 out of 94 (26.6%) cases. Alterations of the P53 gene were detected in 12 (12.8%) tumors; eight of these tumors revealed P53 immunoreactivity. A high number of P53 positive and P53 mutated tumors were histologically defined as poorly differentiated G3 (64.0% and 75.0%, respectively). MDM2 immunopositivity was revealed in 36 out of 94 (38.3%) cases. MDM2 amplification occurred in 17 tumors (18.1%); only nine of these tumors exhibited MDM2 immunoreactivity. Overall, MDM2 positivity was not associated with MDM2 amplification in 27 out of 94 tumors (28.7%). There was no significant correlation between MDM2 overexpression and histological grade. However, when the samples were stratified by immunophenotype, the majority of tumors (52.5%) with isolated MDM2 overexpression (dissociated from P53 positivity) were defined histologically as low grade (G1 + G2). These results support the notion that besides P53 alterations, MDM2 gene deregulation seems to be an important event in sarcomas evolution. Additionally, the mechanism of MDM2-mediated degradation of P53 protein, without involving stabilization and inactivation of P53 gene, should be considered for better understanding of all features of tumor progression processes.
Rieske
P
P
Dept. of Molecular Biology, Medical University of Lodz, Poland.
Bartkowiak
J K
JK
Szadowska
A M
AM
Olborski
B
B
Harezga-Bal
B
B
Debiec-Rychter
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D004252:DNA Mutational Analysis; D018223:Dermatofibrosarcoma / Q000737:chemistry / Q000235:genetics; D005260:Female; D005354:Fibrosarcoma / Q000737:chemistry / Q000235:genetics; D005784:Gene Amplification; D016158:Genes, p53; D020180:Heteroduplex Analysis; D006801:Humans; D007890:Leiomyosarcoma / Q000737:chemistry / Q000235:genetics; D008080:Liposarcoma / Q000737:chemistry / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics*; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2; D012326:RNA Splicing; D012509:Sarcoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2