MDM2 gene amplification in colorectal cancer is associated with disease progression at the primary site, but inversely correlated with distant metastasis.
MDM2 is a crucial negative regulator of the TP53 tumor suppressor and almost 10% of human tumors exhibit MDM2 amplification. Although TP53 pathway perturbation has been extensively examined in colorectal cancer (CRC), only one previous report has evaluated MDM2 amplification in relation to clinicopathological factors. In that report, MDM2 amplification was shown to be associated with disease progression from Dukes' Stages A to D. In this study, we investigated MDM2 amplification by quantitative PCR and fluorescence in situ hybridization (FISH) together with the SNP309 genotypes, and analyzed the correlations with TP53 and KRAS mutations and clinicopathological features in 211 Japanese CRC patients. MDM2 amplification was detected in 8% of the specimens and its incidence was significantly higher in Dukes' stage C than in the combined earlier Stages A and B (P = 0.025). Unexpectedly, the incidence was significantly decreased in Stage D metastatic disease (P = 0.043). The copy number gain ranged from four to eight copies and was generally concordant with gain of centromere 12 using FISH analysis. Together with the results of centromere 1 FISH and TP53 copy number assessment, the MDM2 increment most likely resulted from chromosome 12 gain. The mechanism of the copy number gain and incidence in Dukes' Stage D differed considerably from the previous report. Ethnic or geographic factors could be responsible for these differences. Several promising therapeutic strategies targeting the TP53-MDM2 system are being developed. Further understanding of the significance of MDM2 and MDM2 amplification in CRC is required to facilitate personalized treatment for CRC patients.
Sugano
Nobuhiro
N
Department of Gastrointestinal Surgery, Kanagawa Cancer Center Hospital, Yokohama, Japan.
Suda
Tetsuji
T
Godai
Ten-I
TI
Tsuchida
Kazuhito
K
Shiozawa
Manabu
M
Sekiguchi
Hironobu
H
Yoshihara
Mitsuyo
M
Matsukuma
Shoichi
S
Sakuma
Yuji
Y
Tsuchiya
Eiju
E
Kameda
Yoichi
Y
Akaike
Makoto
M
Miyagi
Yohei
Y
D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D005784:Gene Amplification; D011905:Genes, ras; D005838:Genotype; D006801:Humans; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2
C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2