Rare MDM4 gene amplification in colorectal cancer: The principle of a mutually exclusive relationship between MDM alteration and TP53 inactivation is not applicable

Abstract

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.

Case report: A combined immunotherapy strategy as a promising therapy for MSI-H colorectal carcinomas with multiple HPD risk factors

“…On the other hand, MDM2 amplification can induce resistance to ICI by reducing T-cell activation in malignancies (25,26). Although none of these molecular alterations was found in CRC with HPD, which may be related to the 27) demonstrated that the principle of rare MDM4 amplification in CRC is unclear, which is different from the mechanism of a mutually exclusive relationship between MDM2 alteration and TP53 inactivation (27). More importantly, our case carries MDM4 and DNMT3A co-mutation, which have not been reported in CRC by the Cbioportal Database.…”

“…Although none of these molecular alterations was found in CRC with HPD, which may be related to the low prevalence of MDM2/4 amplification (approximately 2%) and DNMT3A mutations (approximately 4%) in CRC. Suda et al ( 27 ) demonstrated that the principle of rare MDM4 amplification in CRC is unclear, which is different from the mechanism of a mutually exclusive relationship between MDM2 alteration and TP53 inactivation ( 27 ). More importantly, our case carries MDM4 and DNMT3A co-mutation, which have not been reported in CRC by the Cbioportal Database.…”

MDMX in Cancer: A Partner of p53 and a p53-Independent Effector

“…Paradoxically, the level of MDMX protein decreases in cases of gene amplification. 56 Therefore, the functional significance of MDMX is still unclear and needs further study. Unlike in hepatocellular carcinoma, TP53 mutation is not a common oncogenic driver in fibrolamellar hepatocellular carcinoma.…”

Targeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges

“…The amplification and overexpression of MDMX in breast cancer have also been confirmed in Nottingham/Tenovus cohort with a well-characterized series of 990 cases and other studies and have been associated with p53 mutation, breast carcinogenesis, invasive disease, small tumor size, low grade, longer breast carcinoma specific survival (BCSS), and disease-free survival (DFS) ( 62 – 65 ). However, MDMX amplification is rare (1.4%) in colon cancer and its functional significance in this disease still needs further investigations ( 66 ). Mancini et al have found that the expression of full-length MDMX ( MDMX-FL ), but not its oncogenic MDMX-S variant is significantly associated with the responses of ovarian cancer patients to chemotherapy ( 67 ).…”