title: Rare MDM4 gene amplification in colorectal cancer: The principle of a mutually exclusive relationship between MDM alteration and TP53 inactivation is not applicable.
abstract: MDM4, a homolog of MDM2, is considered a key negative regulator of p53. Gene amplification of MDM4 has been identified in a variety of tumors. MDM2 or MDM4 gene amplification is only associated with the wild-type TP53 gene in retinoblastomas, thus the amplification of the two genes is mutually exclusive. Previously, we demonstrated that MDM2 amplification and TP53 alteration were not mutually exclusive in colorectal cancer, and we identified a subset of colorectal cancer patients without alterations in either the TP53 or the MDM2 gene. In this study, we investigated the gene amplification status of MDM4 in the same set of colorectal cancer cases. Unexpectedly, MDM4 amplification was rare, detected in only 1.4% (3 out of 211) of colorectal cancer cases. All the three gene-amplified tumors also harbored TP53-inactivating mutations. This contradicts the simple mutually exclusive relationship observed in retinoblastomas. Surprisingly, two of the three MDM4-amplified tumors also demonstrated MDM2 amplification. Paradoxically, the MDM4 protein levels were decreased in the tumor tissue of the gene-amplified cases compared with levels in the matched normal mucosa. We speculate that MDM4 might play a role in colorectal carcinogenesis that is not limited to negative regulation of p53 in combination with MDM2. The functional significance of MDM4 is still unclear and further studies are needed.
authors.affiliation: Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama 241-0815, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Suda
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Yoshihara
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sekiguchi
authors.forename: Ten-I
authors.initials: TI
authors.lastname: Godai
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Sugano
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Tsuchida
authors.forename: Manabu
authors.initials: M
authors.lastname: Shiozawa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sakuma
authors.forename: Eiju
authors.initials: E
authors.lastname: Tsuchiya
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kameda
authors.forename: Makoto
authors.initials: M
authors.lastname: Akaike
authors.forename: Shoichi
authors.initials: S
authors.lastname: Matsukuma
authors.forename: Yohei
authors.initials: Y
authors.lastname: Miyagi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018797:Cell Cycle Proteins; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2