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Cancer Genes and Genomics

MDM2 Gene Amplification Is Correlated to Tumor Progression but not to the Presence of SNP309 or TP53 Mutational Status in Primary Colorectal Cancers

Departments of ¹ Surgery, ² Epidemiology and Biostatistics, and ³ Pathology, Memorial Sloan-Kettering Cancer Center; ⁴ Department of Microbiology, Weill Medical College of Cornell University, New York, New York; ⁵ Department of Pediatrics, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey; and ⁶ Department of Molecular Biology, Princeton University, Princeton, New Jersey

Requests for reprints: Philip Paty, Memorial Sloan-Kettering Cancer Center, Department of Surgery, Colorectal Surgery Service, 1275 York Avenue, New York, NY 10021. Phone: 212-639-6703; Fax: 212-717-3678. E-mail: patyp{at}mskcc.org

Mdm2 is the main regulator of p53 and is amplified in 7% of all human cancers. MDM2 gene amplification as well as expression has been correlated to an increased tumorigenic potential. We have analyzed the prevalence of MDM2 gene amplifications and SNP309 in 284 colorectal tumors using a relatively new highly sensitive PCR/ligase detection reaction method in relation to TP53 mutational status and genomic instability. We found MDM2 to be amplified in 9% of the 284 colorectal cancers analyzed and a significantly higher proportion of tumors with high MDM2 gene amplification retained a wild-type p53 gene (P = 0.058). MDM2 gene amplification was significantly correlated to advanced tumor stage. Several small-molecule MDM2 antagonists have already been identified that either physically inhibit the p53-MDM2 binding or the E3 ligase function of MDM2. Our results suggest that MDM2 is a promising target for this type of cancer therapy in a substantial subgroup of colorectal cancers. (Mol Cancer Res 2008;6(2):205–11)