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BIOMARKER:

MBD4 mutation

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Other names: MBD4, Methyl-CpG Binding Domain 4, DNA Glycosylase, Methyl-CpG-Binding Domain Protein 4, Mismatch-Specific DNA N-Glycosylase, Methyl-CpG Binding Domain Protein 4, Methyl-CpG-Binding Endonuclease 1, Methyl-CpG-Binding Protein MBD4, MED1, G/5-Fluorouracil Mismatch Glycosylase With Biphasic Kinetics, Putative Methyl-CpG Binding Protein, 3,N(4)-Ethenocytosine Glycosylase, G/T Mismatch Glycosylase, G/U Mismatch Glycosylase
Entrez ID:
Related biomarkers:
9ms
MBD4-associated neoplasia syndrome: screening of cases with suggestive phenotypes. (PubMed, Eur J Hum Genet)
Eight CRC patients carried rare homozygous or heterozygous germline variants in MBD4. The information gathered on mode of inheritance, variant nature, functional effect of the variant, and tumour mutational characteristics suggested that none of the patients included in the study had an MBD4-associated hereditary syndrome and that the heterozygous variants identified were not associated with the disease.
Journal
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MBD4 (Methyl-CpG Binding Domain 4, DNA Glycosylase) • MUTYH (MutY homolog)
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MBD4 mutation
over1year
Cytidine analogs are synthetic lethal with base excision repair default due to MBD4 deficiency. (PubMed, NPJ Precis Oncol)
We further confirm the exquisite activity of gemcitabine in an MBD4-deficient co-clinical model as (i) it completely prevented the development of an MBD4-deficient uveal melanoma patient-derived xenograft and (ii) treatment in the corresponding patient resulted in an exceptional tumor response. These data suggest that patients harboring MBD4-deficient tumors may be treated efficiently by cytidine analogs.
Journal • Synthetic lethality
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MBD4 (Methyl-CpG Binding Domain 4, DNA Glycosylase)
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MBD4 mutation
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gemcitabine
over1year
Role of MBD4 Mutation in Neoplastic Evolution of Acute Myeloid Leukemia (ASH 2022)
Consequently, in agreement with our hypothesis, TET2WT cells with loss of MBD4 were significantly more sensitive to olaparib-mediated PARP1 inhibition...1C). Our findings pave the way for consideration of MBD4 as a potential actionable target to regulate DNA methylation in association with TET2 during leukemogenesis.
Tumor Mutational Burden • PARP Biomarker
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TMB (Tumor Mutational Burden) • TET2 (Tet Methylcytosine Dioxygenase 2) • MBD4 (Methyl-CpG Binding Domain 4, DNA Glycosylase)
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TMB-H • TET2 mutation • MBD4 mutation
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Lynparza (olaparib)
over1year
MBD4 deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients. (PubMed, Eur J Cancer)
In mUM patients, MBD4 mutation is highly predictive for the response, PFS, and overall survival benefit to ICI. MBD4 could be a tissue-agnostic biomarker and should be sequenced in mUM, and other tumor types where MBD4 mutations are reported.
Journal • Checkpoint inhibition • IO biomarker
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MBD4 (Methyl-CpG Binding Domain 4, DNA Glycosylase) • LXN (Latexin)
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MBD4 mutation
almost2years
MBD4 deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients: A retrospective study. (ASCO 2022)
In mUM patients, MBD4 mutation is highly predictive for response to ICI, PFS and overall survival benefit. MBD4 could be a tissue-agnostic biomarker and should be sequenced in mUM and other tumor types where MBD4 mutations are reported.
Retrospective data • Checkpoint inhibition • Tumor Mutational Burden • IO biomarker
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TMB (Tumor Mutational Burden) • MBD4 (Methyl-CpG Binding Domain 4, DNA Glycosylase)
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TMB-H • TMB-L • MBD4 mutation
over2years
Germline Biallelic Loss in MBD4 leading to Early Onset AML with Hyper-Mutator Genomic Signature (ASH 2021)
Genomic profiling of the normal and affected tissue identified germline bi-allelic loss of function mutation in MBD4 as initiator of methylation defect in key driver genes in tissue specific manner leading to carcinogenesis. This conserved path to mutagenesis is unique to this cancer predisposition syndrome and further biological studies are needed to fully understand the spectrum of cancers associated with this syndrome.
Tumor Mutational Burden
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TMB (Tumor Mutational Burden) • FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • MBD4 (Methyl-CpG Binding Domain 4, DNA Glycosylase)
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TMB-H • DNMT3A mutation • NF2 mutation • MBD4 mutation • DNMT3A R882
over3years
[VIRTUAL] Germline loss of function variants in the base excision repair gene MBD4 cause a Mendelian recessive syndrome of adenomatous colorectal polyposis and AML (NCRI 2020)
We advise that MBD4 should be included in germline mutation testing panels for polyposis and/or early-onset AML. Impact statement Germline biallelic loss of MBD4 predisposes to a rare recessive inherited syndrome characterised by colorectal polyposis and AML.
Tumor Mutational Burden
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TMB (Tumor Mutational Burden) • MBD4 (Methyl-CpG Binding Domain 4, DNA Glycosylase)
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MBD4 mutation
over3years
Evolutionary routes in metastatic uveal melanomas depend on MBD4 alterations. (PubMed, Clin Cancer Res)
MBD4-proficient UM are stable at the nucleotide level without new actionable alterations when metastatic. In contrast, MBD4 deficiency is associated with high genetic heterogeneity and acquisition of new driver mutations. Monosomy 3 is associated with time to relapse rather than rate of relapse thus opening avenues for a new genetic prognostic classification of UMs.
Journal • Tumor Mutational Burden
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TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • MBD4 (Methyl-CpG Binding Domain 4, DNA Glycosylase) • GNAS (GNAS Complex Locus)
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TMB-L • MBD4 mutation
over3years
Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours. (PubMed, Nat Commun)
All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE).
Journal • Tumor Mutational Burden
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TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • GNAQ (G Protein Subunit Alpha Q) • SF3B1 (Splicing Factor 3b Subunit 1) • BAP1 (BRCA1 Associated Protein 1) • GNA11 (G Protein Subunit Alpha 11) • MBD4 (Methyl-CpG Binding Domain 4, DNA Glycosylase)
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TP53 mutation • TMB-H • TMB-L • GNAQ mutation • SF3B1 mutation • BAP1 mutation • MBD4 mutation
over3years
[VIRTUAL] Treatment of metastatic uveal melanoma (mUM) through genomic profiling (ESMO 2020)
Thirty-nine patients had a treatment recommendation and 25 (64%) of them received a targeted therapy accordingly, based on off-label use of trametinib (14), selumetinib (2), crizotinib (7), cabozantinib (4), palbociclib (1), sorafenib+trametinib (1)...One patient with 459 somatic mutations and a MBD4 mutation had a partial durable response under Nivolumab...Legal entity responsible for the study: Charité Comprehensive Cancer Center, Berlin, Germany Max-Planck-Institut für molekulare Genetik, Berlin, Germany. Funding: Bundesministerium für Bildung und Forschung, Germany Max-Planck-Institut für Molekulare Genetik, Berlin, Germany Charité Comprehensive Cancer Center, Berlin, Germany.
Tumor Mutational Burden • PD(L)-1 Biomarker • IO biomarker
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TMB (Tumor Mutational Burden) • PTEN (Phosphatase and tensin homolog) • BCL2 (B-cell CLL/lymphoma 2) • GNAQ (G Protein Subunit Alpha Q) • SF3B1 (Splicing Factor 3b Subunit 1) • MDM2 (E3 ubiquitin protein ligase) • BAP1 (BRCA1 Associated Protein 1) • GNA11 (G Protein Subunit Alpha 11) • MBD4 (Methyl-CpG Binding Domain 4, DNA Glycosylase)
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BAP1 mutation • MBD4 mutation
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Opdivo (nivolumab) • Mekinist (trametinib) • Xalkori (crizotinib) • Ibrance (palbociclib) • sorafenib • Koselugo (selumetinib) • Cabometyx (cabozantinib tablet)
almost4years
Germline Loss-of-function Variants in MBD4 are Rare in Finnish Patients with Uveal Melanoma. (PubMed, Pigment Cell Melanoma Res)
Thus, our data do not support the suggestion that MBD4 germline variants predispose to UM. Somatic loss of MBD4 might modify the mutational burden in UM and change its response to immune checkpoint inhibitors.
Clinical • Journal • Tumor Mutational Burden • BRCA Biomarker
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TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BAP1 (BRCA1 Associated Protein 1) • MBD4 (Methyl-CpG Binding Domain 4, DNA Glycosylase)
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BAP1 mutation • MBD4 mutation