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    BIOMARKER:

    MDM4 amplification

    i
    Other names: MDM4, The mouse double minute 4, MDM4 Regulator Of P53, Mdm2-Like P53-Binding Protein, MDM4, P53 Regulator, Double Minute 4, Human Homolog Of; P53-Binding Protein, P53-Binding Protein Mdm4, Double Minute 4 Protein
    Entrez ID:
    4194
    Related biomarkers:
    Expression
    Mutation
    2d
    ALRN-6924 and Paclitaxel in Treating Patients With Advanced, Metastatic, or Unresectable Solid Tumors (clinicaltrials.gov)
    P1, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Phase classification: P1b --> P1
    Phase classification • Combination therapy • Metastases
    |
    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase) • MDM4 (The mouse double minute 4) • GDF15 (Growth differentiation factor 15) • CASP3 (Caspase 3) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
    |
    ER positive • HER-2 negative • TP53 wild-type • MDM4 amplification • MDM2 mutation • TP53 amplification
    |
    paclitaxel • ALRN-6924
    5ms
    Clinicopathologic characterization of diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype: an aggressive and genomically complex group of tumors affecting children and adults (SNO 2023)
    Overall, while the pediatric and adult pHGG have similar outcomes, there are differences in their genomic structures, most notably in adult pHGG harboring a higher SCNA load. Overall, pHGG represent a biologically diverse set of clinically aggressive tumors that warrant further intensive study.
    Clinical
    |
    EGFR (Epidermal growth factor receptor) • MET (MET proto-oncogene, receptor tyrosine kinase) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • MGMT (6-O-methylguanine-DNA methyltransferase) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor) • CDK4 (Cyclin-dependent kinase 4) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • MDM4 (The mouse double minute 4) • CDK6 (Cyclin-dependent kinase 6)
    |
    MET amplification • CDKN2A deletion • MYCN amplification • MGMT promoter methylation • RB1 deletion • MDM4 amplification • IDH wild-type • RB deletion • CDK6 amplification
    6ms
    ALRN-6924 and Paclitaxel in Treating Patients With Advanced, Metastatic, or Unresectable Solid Tumors (clinicaltrials.gov)
    P1b, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jul 2023 --> Apr 2025 | Trial primary completion date: Jul 2023 --> Apr 2025
    Trial completion date • Trial primary completion date • Combination therapy • Metastases
    |
    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase) • MDM4 (The mouse double minute 4)
    |
    ER positive • HER-2 negative • TP53 wild-type • MDM4 amplification • TP53 amplification
    |
    paclitaxel • ALRN-6924
    12ms
    Prevalence, causes and impact of TP53-loss phenocopying events in human tumors. (PubMed, BMC Biol)
    Human tumors that do not bear obvious TP53 genetic alterations but that phenocopy p53 activity loss are common, and the USP28 gene deletions are one likely cause.
    Journal
    |
    TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • MDM4 (The mouse double minute 4) • PPM1D (Protein Phosphatase Mg2+/Mn2+ Dependent 1D)
    |
    TP53 mutation • PIK3CA mutation • PTEN mutation • MDM4 amplification
    almost1year
    ALRN-6924 and Paclitaxel in Treating Patients With Advanced, Metastatic, or Unresectable Solid Tumors (clinicaltrials.gov)
    P1b, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting
    Enrollment closed • Combination therapy • Metastases
    |
    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase) • MDM4 (The mouse double minute 4)
    |
    ER positive • HER-2 negative • TP53 wild-type • MDM4 amplification • TP53 amplification
    |
    paclitaxel • ALRN-6924
    1year
    MDM4 amplification in atypical lipomatous tumors/ well-differentiated liposarcoma: private event or alternative oncogenic mechanism? (PubMed, Genes Chromosomes Cancer)
    This report shows that MDM4 amplification is an exceptional molecular event alternative to MDM2 amplification in ALT/WDLPS. This alteration should be considered and looked for in suspicious adipocytic tumors to optimize their surgical management.
    Journal
    |
    MDM2 (E3 ubiquitin protein ligase) • MDM4 (The mouse double minute 4)
    |
    MDM2 amplification • MDM4 amplification
    almost2years
    MDM2/MDM4 amplification and CDKN2A deletion in metastatic melanoma and glioblastoma multiforme may have implications for targeted therapeutics and immunotherapy. (PubMed, Am J Cancer Res)
    In 592 GBM samples we found that 8.45% display MDM2 amplification. We suggest that patients with melanoma or GBM and amplifications in MDM2/4 and CDKN2A alterations may benefit from combinations of targeted inhibitors of MDM2/4 and CDK4/6, as well as immunotherapy.
    Journal • IO biomarker
    |
    CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NF1 (Neurofibromin 1) • MDM2 (E3 ubiquitin protein ligase) • LRP1B (LDL Receptor Related Protein 1B) • CDK4 (Cyclin-dependent kinase 4) • MUC16 (Mucin 16, Cell Surface Associated) • MDM4 (The mouse double minute 4) • PPM1D (Protein Phosphatase Mg2+/Mn2+ Dependent 1D)
    |
    TP53 wild-type • MDM2 amplification • CDKN2A deletion • MDM4 amplification
    almost2years
    Genetic and immunohistochemical profiling of small cell and large cell neuroendocrine carcinomas of the breast. (PubMed, Mod Pathol)
    NEC and IDC-NST components of mixed tumors were clonally related and immunophenotypically distinct, lacking ER and GATA3 expression in NEC relative to IDC-NST, with RB loss only in NEC of one ANEC. The findings provide insight into the pathogenesis of breast NEC, underscore their classification as a distinct tumor type, and highlight genetic similarities to extramammary NEC, including highly prevalent p53/RB pathway aberrations in SCNEC.
    Journal
    |
    ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • RB1 (RB Transcriptional Corepressor 1) • MDM2 (E3 ubiquitin protein ligase) • CDH1 (Cadherin 1) • MDM4 (The mouse double minute 4) • GATA3 (GATA binding protein 3)
    |
    ER negative • MDM4 amplification • CDH1 mutation • RB1 negative
    almost2years
    A pancancer analysis of impact of MDM2/MDM4 on immune checkpoint blockade (ICB). (ASCO 2022)
    MDM2 and MDM4 amplification are negative prognostic factors in TP53-WT breast cancer while MDM4 amp is associated with reduced survival in ICB-treated NSCLC.
    Checkpoint inhibition • PD(L)-1 Biomarker • IO biomarker • Pan tumor
    |
    EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • STK11 (Serine/threonine kinase 11) • ARID1A (AT-rich interaction domain 1A) • KEAP1 (Kelch Like ECH Associated Protein 1) • MDM2 (E3 ubiquitin protein ligase) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • MDM4 (The mouse double minute 4)
    |
    PD-L1 expression • KRAS mutation • EGFR mutation • BRAF mutation • PIK3CA mutation • TP53 wild-type • PTEN mutation • ARID1A mutation • STK11 mutation • KEAP1 mutation • MDM4 amplification • MDM2 overexpression
    |
    PD-L1 IHC 22C3 pharmDx
    2years
    A comprehensive pan-cancer analysis of MDM2/MDM4 gene amplification in Chinese solid cancer patients (AACR 2022)
    Although amplification of MDM2/MDM4 was observed only in a small proportion of patients, it demonstrated an association with high TMB in several common cancer types. In addition, our data indicate that amplification of MDM2/MDM4 in different types of cancer is heterogeneous and that an appropriate immunotherapy strategy for patients with solid cancer should be noted.
    Clinical • PD(L)-1 Biomarker • IO biomarker • Pan tumor
    |
    TMB (Tumor Mutational Burden) • MDM2 (E3 ubiquitin protein ligase) • MDM4 (The mouse double minute 4)
    |
    TMB-H • MDM4 amplification
    2years
    MDM2/MDM4 amplification and CDKN2A deletion in melanoma brain metastases and GBM may have implications for targeted therapeutics and immunotherapy (AACR 2022)
    Given the genomic similarities between melanoma and glioblastoma, we suggest that patients with melanoma or GBM and amplifications in MDM2/4 and CDKN2A deletions may need the development of combinations of targeted inhibitors of MDM2/4, CDK’s and immunotherapy. We are currently pursuing these translational directions.
    Late-breaking abstract • IO biomarker
    |
    CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NF1 (Neurofibromin 1) • MDM2 (E3 ubiquitin protein ligase) • LRP1B (LDL Receptor Related Protein 1B) • MUC16 (Mucin 16, Cell Surface Associated) • MDM4 (The mouse double minute 4) • PPM1D (Protein Phosphatase Mg2+/Mn2+ Dependent 1D) • SERPINB4 (Serpin Family B Member 4)
    |
    TP53 wild-type • MDM2 amplification • CDKN2A deletion • MDM4 amplification
    2years
    Analysis of genetic alterations related to hyper-progressive disease after immunotherapy in patients with non-small cell lung cancer (AACR 2022)
    Conversely, patients with TMB-high showed lower copy number gain in MDM2/4. However, no difference was found in level of PD-L1 expression between patients with and without MDM2/4 amplification.Conclusion HPD happened during ICI treatment in solid tumor with MDM2/4 amplification may associated with lower TMB level, and PD-L1 expression level has limit effect on MDM2/4 alteration related HPD.
    Clinical • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker
    |
    EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • MDM2 (E3 ubiquitin protein ligase) • MDM4 (The mouse double minute 4)
    |
    PD-L1 expression • EGFR mutation • TMB-H • MDM4 amplification
    |
    PD-L1 IHC 22C3 pharmDx
    2years
    Clinical and Genetic Characteristics of Thymoma Patients With Autoimmune Hepatitis and Myocarditis. (PubMed, Front Oncol)
    Our study reveals the clinical and genetic characteristics of thymoma patients with autoimmune hepatitis and myocarditis. For this special category of thymoma, the up-regulation of p53 and mdm4 plays an important role in the occurrence of thymoma and autoimmune hepatitis/myocarditis.
    Journal
    |
    MDM4 (The mouse double minute 4) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
    |
    MDM4 amplification • TP53 expression
    over2years
    Clinical Application of Next Generation Sequencing in Glioblastoma : An Institutional Experience (USCAP 2022)
    The current treatment, which has remained largely unchanged for the last decade, is surgical resection followed by radiotherapy and temozolomide... In all the cases in our cohort, NGS was able to provide diagnostically, prognostically and therapeutically relevant information. We conclude that NGS can be a useful tool for guiding patient management for the WHO grade IV glioblastoma. Further work is needed to determine whether NGS is changing patient management and improving clinical outcomes..
    Clinical • Next-generation sequencing
    |
    EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • PTEN (Phosphatase and tensin homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • FGFR3 (Fibroblast growth factor receptor 3) • TERT (Telomerase Reverse Transcriptase) • TACC3 (Transforming acidic coiled-coil containing protein 3) • MDM2 (E3 ubiquitin protein ligase) • CDK4 (Cyclin-dependent kinase 4) • MDM4 (The mouse double minute 4) • CCND2 (Cyclin D2)
    |
    TP53 mutation • KRAS mutation • EGFR mutation • IDH1 mutation • PTEN mutation • FGFR3 mutation • CDK4 amplification • MDM4 amplification • TERT mutation • EGFR mutation + PTEN mutation • CDK4 mutation
    |
    Oncomine™ Comprehensive Assay v3M
    |
    temozolomide
    over2years
    Response Stratification in the First-Line Combined Immunotherapy of Hepatocellular Carcinoma at Genomic, Transcriptional and Immune Repertoire Levels. (PubMed, J Hepatocell Carcinoma)
    Patients received sorafenib/sintilimab or lenvatinib/sintilimab combined first-line therapy and the response was assessed at 3-6 cycles of therapy. MDM4 was capable of predicting disease progression, and a panel mRNA and lncRNA of eight genes may also predict the response. Further validation is needed to verify these biomarkers.
    Clinical • Journal • IO biomarker
    |
    TP53 (Tumor protein P53) • TERT (Telomerase Reverse Transcriptase) • FGF3 (Fibroblast growth factor 3) • CXCL10 (Chemokine (C-X-C motif) ligand 10) • MDM4 (The mouse double minute 4) • TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains 2) • CD34 (CD34 molecule) • CXCL9 (Chemokine (C-X-C motif) ligand 9) • ICAM1 (Intercellular adhesion molecule 1) • ERN1 (Endoplasmic Reticulum To Nucleus Signaling 1)
    |
    TP53 mutation • MDM4 amplification
    |
    sorafenib • Tyvyt (sintilimab) • Lenvima (lenvatinib)
    over2years
    Clonal Hematopoiesis Driven By MDM4 Amplification Defines a Canonical Route Towards Secondary MDS/AML in Fanconi Anemia Patients (ASH 2021)
    Conclusions The somatic genomic landscape of FA MDS/AML reveals a unique FA mutational signature, characterized by structural rearrangements and copy number abnormalities rather than point mutations. Our results define a canonical oncogenic route towards secondary MDS/AML in FA patients, in which the early modulation of the p53 pathway through 1q+/MDM4 oncogene overexpression plays a pivotal role, raising novel monitoring and therapeutic prospects for the FA patients.
    Clinical • BRCA Biomarker
    |
    HRD (Homologous Recombination Deficiency) • RUNX1 (RUNX Family Transcription Factor 1) • BRCA (Breast cancer early onset) • MDM4 (The mouse double minute 4)
    |
    FANCA mutation • MDM4 amplification • BRCA mutation
    over2years
    Intimal sarcomas and undifferentiated cardiac sarcomas carry mutually exclusive MDM2, MDM4, and CDK6 amplifications and share a common DNA methylation signature. (PubMed, Mod Pathol)
    We further report novel co-amplifications of various oncogenes, which may have therapeutic implications. Finally, the genetic and epigenetic concordance of ISAs and UPS of the left atrium further supports a shared pathogenesis and common classification.
    Journal • Epigenetic controller
    |
    CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • CCND1 (Cyclin D1) • MDM2 (E3 ubiquitin protein ligase) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor) • CDK4 (Cyclin-dependent kinase 4) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • MDM4 (The mouse double minute 4) • CDK6 (Cyclin-dependent kinase 6)
    |
    MDM2 amplification • CDKN2A deletion • CCND1 amplification • MDM4 amplification • CDK6 amplification
    almost3years
    Genomic and transcriptomic analyses of breast cancer primaries and matched metastases in AURORA, the Breast International Group (BIG) molecular screening initiative. (PubMed, Cancer Discov)
    ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could impact treatment strategies in MBC.
    Journal
    |
    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • RB1 (RB Transcriptional Corepressor 1) • ARID1A (AT-rich interaction domain 1A) • CDH1 (Cadherin 1) • MDM4 (The mouse double minute 4) • GATA1 (GATA Binding Protein 1)
    |
    TP53 mutation • TMB-H • HER-2 negative • PIK3CA mutation • PTEN mutation • ARID1A mutation • MYC amplification • RB1 mutation • ARID1A deletion • MDM4 amplification • MDM4 mutation
    almost3years
    [VIRTUAL] An investigation on biomarkers of hyperprogressive disease after PD-1/PDL-1 therapies in Chinese non-small cell lung cancer patients. (ASCO 2021)
    It is urgent to identify specific biomarkers that could predict HPD and to develop effective methods to prevent HPD . Our study investigated the genomic alterations associated with HPD in Chinese NSCLC patients.
    Clinical • PD(L)-1 Biomarker • IO biomarker
    |
    EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • ALK (Anaplastic lymphoma kinase) • PTEN (Phosphatase and tensin homolog) • STK11 (Serine/threonine kinase 11) • DNMT3A (DNA methyltransferase 1) • KEAP1 (Kelch Like ECH Associated Protein 1) • MDM2 (E3 ubiquitin protein ligase) • FGF3 (Fibroblast growth factor 3) • MDM4 (The mouse double minute 4)
    |
    PD-L1 expression • EGFR mutation • PTEN mutation • STK11 mutation • DNMT3A mutation • ALK fusion • MDM2 amplification • KEAP1 mutation • MDM4 amplification • ALK negative • EGFR mutation + PTEN mutation
    almost3years
    [VIRTUAL] Profiling 523 cancer associated genes in circulating tumor DNA of children with CNS tumors. (ASCO 2021)
    This proof-of-concept study demonstrates the feasibility of our high depth, targeted sequencing approach for detecting clinically relevant mutations in ctDNA from children with CNS tumors . This approach may aid in diagnosis of CNS tumor molecular subtype, and monitoring of tumor evolution and response to therapy in serially collected ctDNA.
    Clinical • Circulating tumor DNA
    |
    KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • MDM4 (The mouse double minute 4) • ACVR1 (Activin A Receptor Type 1) • PPM1D (Protein Phosphatase Mg2+/Mn2+ Dependent 1D)
    |
    TP53 mutation • H3.3K27M • MDM4 amplification • PIK3CA E545
    |
    TruSight Oncology 500 Assay
    over3years
    Targeted sequencing reveals the somatic mutation landscape in a Swedish breast cancer cohort. (PubMed, Sci Rep)
    KMT2C regulates enhancer activation and assists tumor proliferation in a hormone-rich environment, possibly pointing to a role in ER + BC, especially in older cases. Finally, age of onset appears to affect the mutational landscape suggesting that a larger age-diverse population incorporating more molecular subtypes should be studied to elucidate the underlying mechanisms.
    Journal
    |
    ER (Estrogen receptor) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • ARID1A (AT-rich interaction domain 1A) • KMT2C (Lysine Methyltransferase 2C) • CDH1 (Cadherin 1) • MDM4 (The mouse double minute 4)
    |
    TP53 mutation • ER positive • PIK3CA mutation • ARID1A mutation • KMT2C mutation • MDM4 amplification
    over3years
    [VIRTUAL] The biomarkers associated with hyperprogression (HP) to immune checkpoint inhibitors (ICIs) in Chinese hepatocellular carcinoma (HCC) patients (ESMO 2020)
    Legal entity responsible for the study: Hunan Provincial People's Hospital. Funding: Has not received any funding.
    Clinical • Checkpoint inhibition • Tumor Mutational Burden • IO biomarker
    |
    EGFR (Epidermal growth factor receptor) • TMB (Tumor Mutational Burden) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • DNMT3A (DNA methyltransferase 1) • CCND1 (Cyclin D1) • MDM2 (E3 ubiquitin protein ligase) • FGF19 (Fibroblast growth factor 19) • FGF3 (Fibroblast growth factor 3) • MDM4 (The mouse double minute 4) • FGF4 (Fibroblast growth factor 4)
    |
    MDM4 amplification
    almost4years
    Genetic alterations in epidermal growth factor receptor-tyrosine kinase inhibitor-naïve non-small cell lung carcinoma. (PubMed, Oncol Lett)
    Other resistance mechanisms against EGFR-TKIs were indicated in some patients with EGFR-TKI-naïve NSCLC. MDM2 gene amplification, which can lead to altered cell cycle, was associated with tumor recurrence and shorter PFS in EGFR-TKI therapy.
    Journal
    |
    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • FGFR1 (Fibroblast growth factor receptor 1) • CCND1 (Cyclin D1) • CDK4 (Cyclin-dependent kinase 4) • MDM4 (The mouse double minute 4) • CDK6 (Cyclin-dependent kinase 6) • CCND2 (Cyclin D2)
    |
    EGFR mutation • HER-2 amplification • MET amplification • EGFR T790M • EGFR C797S • MDM4 amplification
    almost4years
    [VIRTUAL] Molecular alterations with hyperprogression in lung cancer patients treated with immune checkpoint inhibitors in a large health system. (ASCO 2020)
    Out of 1536 lung cancer patients 350 (22.8%) were treated with ICI including: atezolizumab (35), durvalumab (6), nivolumab (177), pembrolizumab (145). Only the STK11/LKB1 mutation was associated with HP (P = < 0.0001) with 5 of 6 STK11 pts treated with ICI showing HP. Other potential HP biomarkers will be assessed prospectively as larger panels are utilized. Research Funding: None
    Clinical • Checkpoint inhibition • PD(L)-1 Biomarker • IO biomarker
    |
    EGFR (Epidermal growth factor receptor) • STK11 (Serine/threonine kinase 11) • MDM4 (The mouse double minute 4)
    |
    STK11 mutation • MDM4 amplification
    |
    Keytruda (pembrolizumab) • Opdivo (nivolumab) • Tecentriq (atezolizumab) • Imfinzi (durvalumab)