The MDM2 gene amplification database

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.

Mdm2 Snp309 G allele displays high frequency and inverse correlation with somatic P53 mutations in hepatocellular carcinoma

“…In fact, numerous studies have shown that overexpression of MDM2 is an important event in carcinogenesis; in addition, MDM2 amplification occurs mostly in the absence of p53 mutation, supporting the concept that MDM2 amplification and p53 mutation are alternative mechanisms of p53 dysfunction [8,18,19]. In agreement with our hypothesis, a recent study shows that invasive bladder cancer patients with wild-type SNP309 (T/T) were prone to displaying p53 mutations [20].…”

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

“…The human homolog of the mouse double minute (MDM2) is an oncogene overexpressed in different types of malignancies, including solid tumors, sarcomas and leukemias (Momand et al, 1998). MDM2 plays a central role in cancer development and progression, mainly by antagonizing the p53 tumor suppressor activity.…”

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

“…1 In sarcomas, TP53 (tumor protein p53) mutations are infrequent, 2 but in the wild-type TP53 (TP53 Wt ) tumors, p53 may be inactivated by amplification of the mouse double minute 2 (MDM2) gene (MDM2 Ampl ), in particular, in well-differentiated liposarcomas (WDLS). [3][4][5] Complementary mechanisms have been suggested, 6,7 but it is still unclear whether and how the pathway is inactivated in the remaining tumors.…”