We compared sensitivity and specificity of p16 IHC to MDM2 and CDK4 IHC in the differential diagnosis of ALT-WDLPS (n=19) versus benign adipocytic tumors (n=44) and DDLPS (n=18) versus mimicking sarcomas (n=20).
The three cases in which CGH showed gains in the 12q region were studied specifically for amplifications of MDM2 and CDK4, two genes that have been shown to be amplified in other soft tissue sarcomas.
MDM2/4 antagonists, on the other hand, are likely to be efficacious in malignancies in which MDM2 or MDM4 is overexpressed such as sarcomas, neuroblastomas and specific childhood leukemias.
Overexpression and amplification of several genes (MDM2, CDK4 and SAS) located on chromosome 12q13-15 have been noted to occur in various human sarcomas.
The region q13-15 of chromosome 12 frequently is altered in human sarcomas, and several genes, such as SAS, CDK4, and MDM2, have been found to be amplified in bone and soft tissue sarcomas.
Our knowledge of the molecular biology of sarcomas has progressed considerably over the past year, with major emphasis on the role of p53 and MDM2 gene mutations.
The transgenic mice are predisposed to spontaneous tumor formation, and the incidence of sarcomas observed in the Mdm2-transgenic mice in the presence or absence of functional p53 demonstrates that, in addition to Mdm2-mediated inactivation of p53, there exists a p53-independent role for Mdm2 in tumorigenesis.
Amplification of the MDM2 gene, which maps to chromosome band 12q13 and encodes a p53-binding protein, may result in functional inactivation of p53 and has been observed in various bone and soft tissue sarcomas.
Three well-differentiated liposarcomas with MDM2 amplification coexisted with high-grade dedifferentiated sarcomas, in which MDM2 amplification was also observed.
MDM2 is a wild-p53 inducible protein which may form a complex with p53, abrogating its function, as has been found in human sarcomas and other malignancies. p21WAF1/CIP1 is another protein inducible by wild-type p53, involved in inhibiting cell-cycle progression, through binding to cyclin/cyclin-dependent-kinase complexes.
This article provides an overview of these events in human cancer, highlighting the frequent occurrence of MDM2 amplification in sarcoma and the role of SNP309 and SNP285 in regulating MDM2 expression and cancer risk.
Furthermore, SNP309 was proposed to be associated with accelerated soft tissue sarcoma formation in both hereditary (Li-Fraumeni) and sporadic cases in humans.