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MDM2 overexpression is rare in ovarian carcinoma irrespective of TP53 mutation status
W D Foulkes1, G W Stamp, S Afzal
1Department of Medicine, Montreal General Hospital, QC, Canada.
Abstract:
Somatic mutations in TP53 are seen in many human cancers. In addition, the protein product of the wild-type TP53 can be sequestered by the protein MDM2 (murine double minute 2). This protein is commonly overexpressed in human sarcomas and gliomas, usually as a result of gene amplification. In this study, 43 ovarian carcinomas (OCs) were analysed for aberrations in the TP53 gene by immunohistochemistry (IHC), loss of heterozygosity (LOH) or mutation analysis. The MDM2 gene and its product was studied by Southern blotting and IHC. Over 50% of the OCs studied showed mutations in TP53 by either direct sequencing (19/36, 53%), positive IHC (23,43, 53%) or both, whereas 0/32 had amplification of MDM2 and only 1/37 tumours had positive IHC using the anti-MDM2 antibody IF-2. The solitary example of positive IHC in this series was seen in a mixed müllerian tumour with sarcomatous differentiation and was not accompanied by MDM2 DNA amplification. These results support previous data showing that around 50% of OCs have mutations in TP53 and in addition, suggest that MDM2 is not amplified in OC, but the presence of sarcomatous features in mixed müllerian tumours may result in positive immunohistochemistry with IF-2.
Insights
Over 50% of ovarian carcinomas (OCs) exhibit TP53 gene mutations. Murine double minute 2 (MDM2) amplification was not detected in these OC samples, suggesting MDM2 is not a key driver in this cancer type.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Somatic mutations in the TP53 gene are prevalent across numerous human cancers.
- The wild-type TP53 protein can be inhibited by MDM2 (murine double minute 2) protein, which is frequently overexpressed in sarcomas and gliomas, often due to gene amplification.
Purpose of the Study:
- To investigate aberrations in the TP53 gene and MDM2 gene/protein in ovarian carcinomas (OCs).
- To determine the frequency of TP53 mutations and MDM2 amplification/overexpression in a cohort of 43 OCs.
Main Methods:
- Immunohistochemistry (IHC) for TP53 and MDM2 protein expression.
- Loss of heterozygosity (LOH) analysis for TP53.
- Direct sequencing for TP53 mutation detection.
- Southern blotting for MDM2 gene amplification analysis.
Main Results:
- Over 50% of OCs analyzed showed TP53 mutations via sequencing or IHC.
- No MDM2 gene amplification was detected in 32 OC samples.
- Only one tumor exhibited positive MDM2 IHC, which was a mixed müllerian tumor with sarcomatous features and no associated MDM2 DNA amplification.
Conclusions:
- Approximately 50% of ovarian carcinomas harbor TP53 mutations.
- MDM2 gene amplification is not a common event in ovarian carcinomas.
- Positive MDM2 immunohistochemistry in mixed müllerian tumors may correlate with sarcomatous differentiation rather than MDM2 amplification.
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