Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas.
Genetic alterations in the p53 and mdm2 genes have been reported to occur in soft tissue sarcomas. This study was designed to determine the prevalence and potential clinical value of detected molecular abnormalities and altered patterns of expression of mdm2 and p53 genes in adult soft tissue sarcomas. A cohort of 211 soft tissue sarcomas from adults that were both clinically and pathologically well characterized was analyzed. Monoclonal antibodies directed against mdm2 and p53 proteins were used to measure overexpression of these proteins in the nuclei of cells from sections of these tumors. Seventy-six of 207 tumors had abnormally high levels of mdm2 proteins and 56 of 211 tumors overexpressed p53 protein. Twenty-two cases had abnormally high levels of both mdm2 and p53 proteins based upon immunoreactivity with these antibodies. There was a striking statistically significant correlation between the overexpression of p53 and mdm2 proteins in the same tumor and poor survival (P < 0.05) of the patients. A group of 73 soft tissue sarcomas was chosen for analysis using Southern blots, single strand conformation polymorphisms, and direct DNA sequencing to confirm mdm2 gene amplifications and p53 mutations and correlate these with the results of the immunoreactivities. The overexpression of p53 and mdm2 proteins in the nuclei of tumor cells did not always correlate well with gene amplification at the mdm2 locus or mutation at the p53 gene. The possible reasons for these discrepancies are discussed.
Cordon-Cardo
C
C
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Latres
E
E
Drobnjak
M
M
Oliva
M R
MR
Pollack
D
D
Woodruff
J M
JM
Marechal
V
V
Chen
J
J
Brennan
M F
MF
Levine
A J
AJ
D000328:Adult; D000704:Analysis of Variance; D002467:Cell Nucleus / Q000502:physiology; D015331:Cohort Studies; D004273:DNA, Neoplasm / Q000032:analysis; D005784:Gene Amplification / Q000235:genetics; D017353:Gene Deletion; D015870:Gene Expression / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D012509:Sarcoma / Q000235:genetics*; D012983:Soft Tissue Neoplasms / Q000235:genetics*
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2