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The MDM2 gene amplification database
J Momand1, D Jung, S Wilczynski
1Department of Cell and Tumor Biology, Beckman Research Institute, National Medical Center, 1450 East Duarte Road, Duarte, CA 91010-3000, USA. jmomand@coh.org
Abstract:
The p53 tumor suppressor gene is inactivated in human tumors by several distinct mechanisms. The best characterized inactivation mechanisms are: (i) gene mutation; (ii) p53 protein association with viral proteins; (iii) p53 protein association with the MDM2 cellular oncoprotein. The MDM2 gene has been shown to be abnormally up-regulated in human tumors and tumor cell lines by gene amplification, increased transcript levels and enhanced translation. This communication presents a brief review of the spectrum of MDM2 abnormalities in human tumors and compares the tissue distribution of MDM2 amplification and p53 mutation frequencies. In this study, 3889 samples from tumors or xenografts from 28 tumor types were examined for MDM2 amplification from previously published sources. The overall frequency of MDM2 amplification in these human tumors was 7%. Gene amplification was observed in 19 tumor types, with the highest frequency observed in soft tissue tumors (20%), osteosarcomas (16%) and esophageal carcinomas (13%). Tumors which showed a higher incidence of MDM2 amplification than p53 mutation were soft tissue tumors, testicular germ cell cancers and neuro-blastomas. Data from studies where both MDM2 amplification and p53 mutations were analyzed within the same samples showed that mutations in these two genes do not generally occur within the same tumor. In these studies, 29 out of a total of 33 MDM2 amplification-positive tumors had wild-type p53. We hypothesize that heretofore uncharacterized carcinogens favor MDM2 amplification over p53 mutations in certain tumor types. A database listing the MDM2 gene amplifications is available on the World Wide Web at http://www. infosci.coh.org/mdm2 . Charts of MDM2 amplification frequencies and comparisons with p53 genetic alterations are also available at this Web site.
Insights
The MDM2 gene is amplified in 7% of human tumors, particularly soft tissue tumors, osteosarcomas, and esophageal carcinomas. Amplification of MDM2 and p53 mutations rarely occur together, suggesting distinct carcinogenic pathways.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The p53 tumor suppressor gene is crucial for preventing cancer and is inactivated through various mechanisms in human tumors.
- Key mechanisms of p53 inactivation include gene mutation, association with viral proteins, and interaction with the MDM2 oncoprotein.
- The MDM2 gene itself is frequently upregulated in tumors via gene amplification, increased transcription, and enhanced translation.
Purpose of the Study:
- To review the spectrum of MDM2 abnormalities in human tumors.
- To compare the tissue distribution of MDM2 amplification and p53 mutation frequencies.
- To investigate the relationship between MDM2 amplification and p53 mutations within the same tumors.
Main Methods:
- A comprehensive review of previously published data examining MDM2 amplification.
- Analysis of 3889 tumor samples from 28 distinct tumor types for MDM2 amplification.
- Comparison of MDM2 amplification frequencies with p53 mutation data across different tumor types.
Main Results:
- MDM2 amplification was observed in 7% of the analyzed human tumors across 19 tumor types.
- The highest frequencies of MDM2 amplification were found in soft tissue tumors (20%), osteosarcomas (16%), and esophageal carcinomas (13%).
- MDM2 amplification and p53 mutations were generally mutually exclusive, with 29 out of 33 MDM2 amplification-positive tumors exhibiting wild-type p53.
Conclusions:
- MDM2 amplification is a significant mechanism of p53 regulation in human cancers.
- Certain tumor types, including soft tissue tumors, testicular germ cell cancers, and neuroblastomas, show a higher incidence of MDM2 amplification than p53 mutation.
- The inverse relationship between MDM2 amplification and p53 mutation suggests that distinct etiological factors or carcinogens may drive these different inactivation pathways.