MDM2

Overview

MDM2 is the principal E3 ligase for TP53. In the corpus it appears as a differentially altered gene between ever- and never-metastatic LUAD.

Alterations observed in the corpus

  • One of ten genes differentially altered between ever- and never-metastatic LUAD primaries PMID:37084736.
  • Altered less in LUAD metastases than in primaries PMID:37084736.
  • MDM2 alterations were negatively associated with SETD2 driver mutations in LUAD (q<0.05), indicating mutual exclusivity in the MSK-CHORD cohort PMID:39506116.
  • MDM2 amplifications in 4/17 fusion-negative rhabdomyosarcoma (FN-RMS) patients; detectable in ctDNA; co-amplified with CDK4 at the 12q13-15 locus in one FP-RMS tumor PMID:37730754.
  • MDM2 amplification confirmed by FISH in a well-differentiated liposarcoma (WDLS) specimen (SARC0120) in the UCLA sarcoma PDTO biobank; MDM2 amplification preserved in the matched patient-derived tumor organoid (PDTO), demonstrating PDTO fidelity for key sarcoma drivers. PMID:39305899
  • MDM2 included as a biologically relevant gene in cfDNA profiling of 201 metastatic urothelial carcinoma patients in the CALGB 90601 trial (MSK-ACCESS panel, 129 genes); MDM2 was negatively associated with SETD2 driver mutations in LUAD in the MSK-CHORD cohort. PMID:40256659
  • Altered (e.g. amplification) in 14% of GBM samples as part of the p53 pathway PMID:18772890.
  • Focal 12q amplification in ~90% of DDLS; sustained MDM2 shRNA knockdown (>1 week) impaired proliferation in DDLS cell lines; co-amplified with YEATS4 on 12q, supporting cooperative repression of the p53 network; rationale for p53–MDM2 antagonists (nutlin-3a) in DDLS (sarc_mskcc, n=207) PMID:20601955.
  • Amplification identified in p53 pathway context in 188 primary LUAD tumours (TSP cohort); part of the p53 pathway altered in a subset of LUAD. PMID:18948947
  • MDM2 amplification in 9% of metastatic UC samples (UC-GENOME cohort) PMID:36333289
  • MDM2 amplification in 11% of GBC PMID:36228155
  • MDM2 expression and copy number were profiled across 947 cancer cell lines in the CCLE pharmacogenomic study, providing a resource for correlating MDM2 status with drug sensitivity PMID:22460905
  • MDM2 amplification is a recurrent event in breast cancer; enriched in the IntClust 2 subtype within the METABRIC cohort of ~2,000 tumors PMID:22522925
  • Driver amplifications identified by copy number analysis in breast cancer WES (100 tumors, Sanger cohort) PMID:22722201
  • MDM2 amplification observed in lung squamous cell carcinoma (3% of 178 tumors in TCGA cohort) PMID:22960745
  • Copy-number amplification more frequent in Luminal B breast cancer (TCGA, 510 tumors) PMID:23000897
  • Amplification in 5% of high-grade urothelial bladder tumors; nonoverlapping with TP53 mutation PMID:23897969
  • Recurrent focal amplification in GBM; chr12 double-minute amplification of MDM2/CDK4 was identified as a striking structural finding; MDM2 amplification is mutually exclusive with TP53 mutation (p=0.0003) PMID:24120142
  • Focal amplification identified in TCC bladder cancer (UCGC cohort, n=99) PMID:24121792
  • Amplification at the 12q15 amplicon (9%, PFN-skewed) in rhabdomyosarcoma; co-amplified with FRS2; MDM2 amplification is mutually exclusive with TP53 mutation in this context PMID:24436047
  • Focal amplification in 9% of muscle-invasive bladder carcinoma tumors; amplification is an alternative mechanism of TP53 inactivation, with MDM2 amp and TP53 mutation being mutually exclusive events PMID:24476821
  • MDM2 recurrent focal amplification identified as a significant GISTIC peak in LUAD (TCGA, n=230) PMID:25079552
  • MDM2 focal amplifications enriched in Triple-WT cutaneous melanoma subtype (TCGA 333-sample cohort); rationale for MDM2 inhibitors (nutlin-3, AMG-232) in this subtype PMID:26091043
  • Combined TP53/MDM2 alterations depleted in UTUC vs UCB (35.6% vs 62.7%, p=0.001); MDM2-altered tumors carried high CNA burden PMID:26278805
  • Focal amplification in 1-3 desmoplastic melanoma tumors; IHC-confirmed protein-level overexpression PMID:26343386
  • MDM2 amplification observed in pan-lung cancer TCGA analysis (n=1144) as a copy-number alteration in lung adenocarcinoma and squamous cell carcinoma PMID:27158780
  • Amplification in 1 adenoid cystic carcinoma (ACYC) patient directed treatment with an MDM2 inhibitor on a basket trial PMID:27442865
  • Focal amplifications in cisplatin-resistant GCT, mutually exclusive with TP53 alteration; 71% of MDM2-amplified tumors are cisplatin resistant; therapeutic target via nutlin-3 and other MDM2 inhibitors; MYCN amplification predicts MDM2-inhibitor sensitivity in TP53-wild-type tumors PMID:27646943
  • MDM2 co-overexpression with CDK4 in neuroblastoma (NBL) in a pediatric precision-oncology cohort; enrolled on the NEPENTHE trial (NCT02780128) PMID:28007021
  • MDM2 recurrent focal amplification in esophageal squamous cell carcinoma (ESCC) PMID:28052061
  • Copy gain in metastases-only; MDM2:GNS and MDM2:CCT2 RNA fusions detected in acral lentiginous melanoma (ALM) integrated genomic study (34 patients) PMID:28373299
  • Amplification in 1/19 sequenced cases; observed in 1p/19q-intact glioblastoma-like tumors rather than true 1p/19q-codeleted oligodendroglioma PMID:28472509
  • Alterations rise stepwise with tumor stage and grade in NMIBC (p < 0.001); co-altered with TP53 in the p53-pathway axis PMID:28583311
  • Recurrent oncogene amplification in cholangiocarcinoma (n=9 WGS cases) PMID:28667006
  • MDM2 amplification (copy number >4) was found in 6% and MDM2 overexpression (>2-fold above median) in 19% of muscle-invasive bladder cancer (MIBC) tumors; the TP53/Cell Cycle pathway (including MDM2) was inactivated in 89% of tumors; MDM2 and TP53 alterations were mutually exclusive (q < 0.2) PMID:28988769
  • MDM2 amplification was present in 100% of dedifferentiated liposarcoma (DDLPS) by definition; MDM2, CDK4, and HMGA2 co-amplification at 12q13~15 is the defining hallmark of DDLPS; MDM2 amplification, CDK4 amplification, JUN amplification, and TERT amplification distinguished DDLPS from other sarcoma subtypes PMID:29100075
  • Amplification identified in 8 NSCLC patients; PFS not significantly different from overall cohort (HR 1.4, P=.44); hyperprogression signal on anti-PD-(L)1 therapy previously reported elsewhere was not reproduced PMID:29337640

Cancer types (linked)

  • LUAD — differential alteration pattern between metastatic and non-metastatic primaries in the MSK cohort (n=2,532) PMID:37084736.
  • Rhabdomyosarcoma (FN-RMS) — amplification in ~24%; ctDNA-detectable; co-amplified with CDK4 at 12q13-15 in FP-RMS PMID:37730754.
  • WDLS — MDM2 amplification preserved in PDTO from SARC0120; key diagnostic and potential therapeutic marker in liposarcoma. PMID:39305899
  • BLCA (metastatic urothelial carcinoma) — included in MSK-ACCESS cfDNA panel gene set for mUC patients; no specific survival associations reported for MDM2 alone in this cohort. PMID:40256659

Co-occurrence and mutual exclusivity

  • None reported.

Therapeutic relevance

  • None reported.
  • CRT upregulates the p53/MDM2 axis in human cervix tumor cells per ROBIN METEOR Project 1 preliminary data, suggesting MDM2 as a potential translational target in CRT-remodeled cervical tumor microenvironments PMID:41941260.

Open questions

  • None noted.

Sources

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