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BIOMARKER:

KDM6A mutation

i
Other names: KDM6A, Lysine Demethylase 6A, KABUK2
Entrez ID:
Related biomarkers:
8ms
Inherited KDM6AA649T facilitates tumor-immune escape and exacerbates colorectal signet-ring cell carcinoma outcomes. (PubMed, Oncogene)
Besides, expression of KDM6AA694T in immune cells suppresses inflammatory macrophage response and effector T cell response. In conclusion, we characterized a novel inherited KDM6AA694T mutant from a childhood-onset SRCC case and demonstrated that the mutant with impaired H3K27me3 demethylase activity could potentiate tumor malignancy and suppress antitumor immunity.
Journal
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KDM6A (Lysine Demethylase 6A)
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KDM6A mutation • KDM6A expression
1year
Ipsilateral synchronous papillary renal neoplasm with reverse polarity and urothelial carcinoma in a renal transplant recipient: a rare case report with molecular analysis and literature review. (PubMed, Diagn Pathol)
We report here for the first time an extraordinarily rare case of synchronous renal tumors of a PRNRP and UC in the ipsilateral kidney of an RTR. We identified simultaneous KRAS, FGFR3, and KDM6A mutations in two different renal masses in the ipsilateral kidney. Pathologic assessment with comparative molecular analysis of mutational profiles facilitates tumor studies after RT and may be of great value in clinical management strategies.
Review • Journal
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KRAS (KRAS proto-oncogene GTPase) • FGFR3 (Fibroblast growth factor receptor 3) • KDM6A (Lysine Demethylase 6A)
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KRAS mutation • KRAS G12D • FGFR3 mutation • FGFR3 S249C • KRAS G12 • KRAS exon 2 mutation • KDM6A mutation
1year
Mutations in Histone Lysine Methyltransferase Genes Are Associated with Autoimmune Cytopenias (ASH 2023)
Conclusion We report for the first time that patients with autoimmune cytopenias have a high frequency of variants in MT genes. Median allelic frequency close to 50% suggests potential germline predisposition to immune dysregulation and autoimmunity however further studies are needed to better understand the impact of these observations.
Epigenetic controller
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KMT2A (Lysine Methyltransferase 2A) • KMT2D (Lysine Methyltransferase 2D) • KMT2C (Lysine Methyltransferase 2C) • KDM6A (Lysine Demethylase 6A)
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KMT2D mutation • KMT2C mutation • KDM6A mutation • MLL3 mutation
over1year
Implication of KDM6A in bladder cancer. (PubMed, Pharmacogenomics)
Therapeutic strategies are depicted and organized by tables for a better understanding. This review demonstrates that KDM6A has crucial implications in bladder cancer pathogenesis and treatment.
Review • Journal
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KDM6A (Lysine Demethylase 6A)
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KDM6A mutation
over1year
A narrative review on pathogenetic mechanisms of hyperinsulinemic hypoglycemia in Kabuki syndrome. (PubMed, Endocr Regul)
Understanding this phenomenon may provide valuable insight into the physiological mechanisms of insulin release and into the pathological cascade causing hyperinsulinism in KS. The identification of these molecular targets may open new therapeutic opportunities based on epigenetic modifiers.
Review • Journal
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KMT2D (Lysine Methyltransferase 2D) • KDM6A (Lysine Demethylase 6A)
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KMT2D mutation • KDM6A mutation
over1year
NEXT-GENERATION SEQUENCING-BASED GENOMIC PROFILING OF CHILDREN WITH ACUTE MYELOID LEUKEMIA. (PubMed, J Mol Diagn)
Comparison of the mutational landscape at diagnosis and relapse revealed an enrichment of mutations in tumor suppressor genes (16.2% vs. 44.4%) and transcription factors (35.1 vs. 55.6%) at relapse. Our findings shed further light on the heterogeneity of pediatric AML and identified previously unappreciated alterations that may lead to improved molecular characterization and risk stratification of pediatric AML.
Journal • Next-generation sequencing
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • WT1 (WT1 Transcription Factor) • KDM6A (Lysine Demethylase 6A) • STAG2 (Stromal Antigen 2) • CUX1 (cut like homeobox 1) • PHF6 (PHD Finger Protein 6) • BCORL1 (BCL6 Corepressor Like 1)
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TP53 mutation • KDM6A mutation • STAG2 mutation • WT1 mutation • PHF6 mutation
over1year
A novel cuproptosis-related lncRNAs signature predicts prognostic and immune of bladder urothelial carcinoma. (PubMed, Front Genet)
Finally, we performed immune infiltration, immune checkpoint and drug sensitivity analyses on four genes (TTN, ARID1A, KDM6A, RB1) that were highly mutated in the high-risk group to evaluate the immune association of risk genes with BLCA. In conclusion, the cuproptosis-related lncRNA markers constructed in this study have evaluation value for prognosis and immunity in BLCA, which can provide a certain reference for the treatment and immunity of BLCA.
Journal
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RB1 (RB Transcriptional Corepressor 1) • ARID1A (AT-rich interaction domain 1A) • KDM6A (Lysine Demethylase 6A)
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ARID1A mutation • KDM6A mutation
over1year
ISOLATED NON-OCULAR EXTRAMEDULLARY RELAPSE AFTER TREATMENT WITH ANTICD19 CAR-T CELL THERAPY IN A PATIENT WITH HIGH-RISK B-ALL (ASPHO 2023)
The relapse was treated with 3-drug re_x005Fu0002induc on, Capizzi-style methotrexate escala on and inotuzumab, and subsequently an -CD19 CAR-T therapy following lymphodeple on with fludarabine and cyclophosphamide. The mechanism of ac on of an -CD19 cell therapies may contribute to the emergence of a dis nct patern of extramedullary recurrence in comparison to tradi onal chemotherapy. Reports have indicated a rela vely high frequency of extramedullary relapse following treatment with blinatumomab. While there have been case reports describing isolated intraocular relapse a er CAR-T- therapy, other extramedullary relapse localiza ons have not been reported.
Clinical • CAR T-Cell Therapy • IO biomarker
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CD19 (CD19 Molecule) • KDM6A (Lysine Demethylase 6A)
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NRAS mutation • KDM6A mutation
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cyclophosphamide • Blincyto (blinatumomab) • methotrexate • Besponsa (inotuzumab ozogamicin) • fludarabine IV
over1year
KDM6 demethylases integrate DNA repair gene regulation and loss of KDM6A sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition. (PubMed, Leukemia)
Olaparib treatment reduced engraftment of KDM6A-mutant-AML-patient-derived xenografts, highlighting synthetic lethality using Poly-(ADP-ribose)-polymerase-(PARP)-inhibition. Crucially, a higher KDM6A expression is correlated with venetoclax tolerance...Corroborating these results, dual targeting of PARP and BCL2 was superior to PARP or BCL2 inhibitor monotherapy in inducing AML apoptosis, and primary AML cells carrying KDM6A-domain mutations were even more sensitive to the combination. Together, our study illustrates a mechanistic rationale in support of a novel combination therapy for AML based on subtype-heterogeneity, and establishes KDM6A as a molecular regulator for determining therapeutic efficacy.
Journal • PARP Biomarker • IO biomarker • Epigenetic controller
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KDM6A (Lysine Demethylase 6A) • BCL2A1 (BCL2 Related Protein A1) • KDM6B (Lysine Demethylase 6B)
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BCL2 expression • KDM6A mutation • KDM6A expression
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Venclexta (venetoclax) • Lynparza (olaparib)
over1year
GENOMIC PROFILING OF UROTHELIAL CARCINOMA IN SITU OF BLADDER (AUA 2023)
We identified CIS lesions having a unique molecular signature and potentially actionable mutations. KDM6A andCCDC138 were commonly mutated, and levels of T-helper and B-cells were highest in stromal regions while CISharbored more PD1-expressing cells.
PD(L)-1 Biomarker • IO biomarker
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PD-1 (Programmed cell death 1) • KMT2D (Lysine Methyltransferase 2D) • KDM6A (Lysine Demethylase 6A) • HMGB1 (High Mobility Group Box 1) • TYK2 (Tyrosine Kinase 2) • AXIN1 (Axin 1) • HNRNPK (Heterogeneous Nuclear Ribonucleoprotein K) • BRD2 (Bromodomain Containing 2) • CANX (Calnexin) • HSP90AB1 (Heat Shock Protein 90 Alpha Family Class B Member 1)
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PD-L1 expression • PD-1 expression • KDM6A mutation • MTOR overexpression • RB1 overexpression
over1year
Differential Occupancy and Regulatory Interactions of KDM6A in Bladder Cell Lines. (PubMed, Cells)
These structures provide a solid means of studying the functions of KDM6A independently of its demethylase activity. Collectively, our work provides important contributions to the understanding of KDM6A malfunction in bladder cancer.
Preclinical • Journal
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KMT2C (Lysine Methyltransferase 2C) • KDM6A (Lysine Demethylase 6A) • HES1 (Hes Family BHLH Transcription Factor 1)
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KDM6A mutation
over1year
KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and drives cell proliferation in bladder cancer. (PubMed, Cancer Res)
Importantly, ATF3 depletion reversed the cell proliferation phenotype induced by KDM6A deficiency. These data establish that KDM6A loss engenders an epigenetic state that drives tumor growth in an ATF3-dependent manner, creating a potentially targetable molecular vulnerability.
Journal
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KDM6A (Lysine Demethylase 6A) • FOXA1 (Forkhead Box A1) • ATF3 (Activating Transcription Factor 3)
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KDM6A mutation
over1year
Comprehensive genomic characterization of early-stage bladder cancer from 438 patients by whole genome- and exome sequencing (AACR 2023)
Here we investigated the landscape of DNA alterations in NMIBC in a large patient cohort of NMIBC samples with paired transcriptomic data and detailed clinical follow-up. We identified several novel genomic alterations; specifically, we showed that 15% of the tumors had genome doublings, and we identified a complex underlying copy number landscape of the region containing FGFR3.
Clinical • Tumor mutational burden
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HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • FGFR3 (Fibroblast growth factor receptor 3) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • CCND1 (Cyclin D1) • KMT2D (Lysine Methyltransferase 2D) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • ERCC2 (Excision repair cross-complementation group 2) • KMT2C (Lysine Methyltransferase 2C) • KDM6A (Lysine Demethylase 6A) • STAG2 (Stromal Antigen 2) • EP300 (E1A binding protein p300) • GIGYF2 (GRB10 Interacting GYF Protein 2)
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TP53 mutation • HER-2 mutation • CDKN2A deletion • KMT2D mutation • RB1 mutation • CCND1 amplification • KDM6A mutation • EP300 mutation • GIGYF2 overexpression
over1year
Different treatment response in several head and neck squamous cell carcinoma (HNSCC) cell lines reflecting underlying genomic and molecular signatures (AACR 2023)
PI3K/mTOR dual inhibition, PI3Kalpha inhibitor, AKT inhibitor, FGFR inhibitor, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, AT2AR inhibitor, Mcl-1 inhibitor, MEK1/2 inhibitor, EZH2 inhibitor, HDAC inhibitor, CDK9 inhibitor, DNMT3 inhibitor, BRD4/BET inhibitor, JAK2 inhibitor, CXCR4 inhibitor, FAK inhibitor, BTK inhibitor, eribulin, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, maybe through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and the modulation of stemness & PD1/PDL1 pathway...All cell lines will be tried to be categorized as TCGA subtypes for the reference of future drug combinations.Cell linesSCC25KBSASCAL27FaDuSCC15SCC9SCC4TW2.6Differ- entiationWellPoorPoorPoorPoorWellWellWellWell, but rapidly replicated, with high hyper-diploidy & complex rearrangementsHPV statusHPV 16/18HPV18--HPV 16/18--HPV 6/11-EGFR statusMediumLowHighHighMediumHighLowMedium to highUnknownDocetaxel sensitivity+++++++++++++ to +++++-+Cisplatin sensitivity+++++++++++++- to +-- to +5-FU sensitivity+++++++++++-+ to ++-- to +Afatinib sensitivity+++- to +-+++++ to +++++++++-Polo-like kinase Inhibitor sensitivity+++++++++++++ to +++- to +-- to +VEGFR2 Inhibitor sensitivity----+++++--++PI3K/ mTOR inhibitorAll cell lines sensitiveCDK4/6 Inhibitor response+++- to ++++++ to +++++++++++++ to +++Western blotsWeak p-AKT & VEGF-A, mild PDL1 and BMI-1, Gli-1(+)Weak p-AKT, mild PDL1 and strong VEGF-A & BMI-1, p16(+)Moderate p-AKT & BMI-1, high PDL1, mild VEGF-AHigh p-AKT & VEGF-A, mild PDL1 & BMI-1High VEGF-A, moderate p-AKT & PDL1, weak BMI-1, Gli-1(+)Weak p-AKT & VEGF-A, mild PDL1 & BMI-1Weak p-AKT, VEGF-A, & BMI-1, moderate PDL1Moderate p-AKT & VEGF-A, strong BMI-1, mild PDL1, Gli-1(+)High p-AKT, PDL1, & VEGF-A and moderate BMI-1NGSCCND1 gain, CDKN2A deletion, FRG1 mutation, HGF mutation, p53 mutation, ATR mutation, SMO mutation, RUNX1T1 mutationSTK11 mutation, PDGFRA mutation, IGF1 mutation, BCOR mutation, EGFR mutation, NOTCH1 mutation, MET mutation, IKZF1 mutation, NFKB1 mutation, DPYD mutation, FGFR4 mutation, BRCA1 mutation, MSH2 mutation, DNMT3A mutationKRAS mutation, MDM2 mutation, TMB-H, AXIN1 loss, RAD51D mutation, NOTCH1/2 mutation, ERBB4 mutation, PALB2 mutation, p53 mutation, POLE mutation, CASP8 mutation, BRCA2 mutation, RNF43 mutation, LRP1B mutation, MET mutationCDKN2A deletion, EGFR amplification, SMAD4 mutation, TMB-H, LRP1B mutation, APC mutation, CASP8 mutation, CREBBP mutation, PIK3CG mutation, NRAS mutation, ABL1 mutation, FGF23 mutation, HGF mutation, ATRX mutation, p53 mutation, ERBB2 mutation, ROS1 mutation, EP300 mutation, NRAS mutation, CDKN1A mutation, KDM6A mutation, FLT4 mutationCCND1 gain, CDKN2A deletion, FLCN mutation, TMB-H, LRP1B mutation, SMAD4 loss, SF3B1 mutation, FAT1 mutation, VHL mutation, NOTCH3 mutation, EPHA5 mutation, p53 mutation, ERCC2 mutationCCND1 gain, EGFR amplification, SMO mutation, ATR mutation, FAT1 loss, NTRK1 mutation, KMT2D mutation, p53 mutation, NOTCH3 mutationCDKN2A deletion, AXIN2 amplification, SMAD3 loss, HRAS mutation, ATR mutation, NF1 mutation. IGF1R mutation, FLCN mutation, KEAP1 mutation, ASXL1 mutation, PMS2 mutationCCND1 gain, NF1 loss, LRP1B mutation, NSD1 mutation, KMT2D mutation, p53 mutation, EPHA2 mutationFAT1 loss, CCND3/FGF10 amplification, PIK3CA H1047R mutation, STK11 mutation, RICTOR/FLCN amplification, VEGF-A amplification , TSC2 mutation, EPHB1 mutation, MAP2K4 mutation, KDM5A mutation, PDGFRB mutation, SETD2 mutation, RPTOR mutation, APC mutation, DDR2 mutation, ATM mutation, MDM2 mutation, p53 mutation, CDK12 mutation, HRAS mutation, MYC mutation, CDK8 mutation, ARID1B lossOutcomesBest; like TCGA CL (HPV+) subtypeLike TCGA basal subtype, but responded to particular treatments eachBasalBasalLike TCGA mesen-chymal subtype (HPV+)Like TCGA CL(HPV-) subtype, different characters between these 3 cell linesCL(HPV-) subtypeCL(HPV-) subtypeWorse; like TCGA EMT subtype (HPV-)Potential treatmentsAll sensitive maybe; Hedgehog inhibitor , HGF/c-MET inhibitor, and I/O could be tried(1) Taxane, cisplatin, PLKi (2) mTORi (3) IGF1Ri, METi, PDGFRi, FGFRi (4) Epigenetics (5) I/O(1) Taxane, cisplatin, 5-FU, PLKi (2) CDK4/6i (3) I/O (4) DDRi (5) KRASi, METi, HERi (6) p53 reactivator and MDM2/Mcl-1 inhibitor(1) Taxane, cisplatin, 5-FU, PLKi (2) CDK4/6i (3) Mild EGFRi response (4) I/O (5) NRASi, FGFRi, HGF/c-METi/ROS1i/HERi (6) p53 reactivator/DDRi/Epigenetics(1) Cisplatin, 5-FU (2) EGFRi and VEGFR2i (3) Weak to PLKi & CDK4/6i (4) I/O (5) mTORi (6) Ephi (7) DDR/Epigenetics (8) p53 reactivator (9) HIFi(1) Taxane and PLKi (2) EGFRi, VEGFR2i, CDK4/6i (3) NTRKi (4) Hedgehog inhibitor (5) DDRi, epigenetics,& p53 reactivator(1) Taxane &5-FU (2) EGFRi (3) HRASi (4) DDRi/Epigenetics (5) I/O (6) IGF1Ri (7) mTORi(1) EGFRi (2) CDK4/6i (3) I/O (4) Epigenetics (5) Ephi (6) p53 reactivator(1) CDK4/6 inhibitor (2) Multi-targeted VEGFR TKI (3) PI3K/AKT/mTOR inhibitor (4) ICIs combination (5) p53 reactivator/ DDR interventions/Epigenetics (6) Dasatinib, HRASi, EphB1/B4 interventions Further NGS analysis may translate these HNSCC cell lines to represent TCGA subtypes for the reference of future drug combinations, esp... Further NGS analysis may translate these HNSCC cell lines to represent TCGA subtypes for the reference of future drug combinations, esp. immunotherapy, basic/translational research, and animal models. LRP1B will be a potential ICIs efficacy biomarker in HNSCC.
Preclinical • Tumor mutational burden • BRCA Biomarker • PD(L)-1 Biomarker • IO biomarker
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HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • ATM (ATM serine/threonine kinase) • STK11 (Serine/threonine kinase 11) • HRAS (Harvey rat sarcoma viral oncogene homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • DNMT3A (DNA methyltransferase 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NOTCH1 (Notch 1) • NF1 (Neurofibromin 1) • KEAP1 (Kelch Like ECH Associated Protein 1) • POLE (DNA Polymerase Epsilon) • AXL (AXL Receptor Tyrosine Kinase) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • CCND1 (Cyclin D1) • MDM2 (E3 ubiquitin protein ligase) • PALB2 (Partner and localizer of BRCA2) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • KMT2D (Lysine Methyltransferase 2D) • LRP1B (LDL Receptor Related Protein 1B) • FGFR4 (Fibroblast growth factor receptor 4) • MSH2 (MutS Homolog 2) • RNF43 (Ring Finger Protein 43) • CDK12 (Cyclin dependent kinase 12) • SMAD4 (SMAD family member 4) • IKZF1 (IKAROS Family Zinc Finger 1) • ERCC2 (Excision repair cross-complementation group 2) • PMS2 (PMS1 protein homolog 2) • VHL (von Hippel-Lindau tumor suppressor) • APC (APC Regulator Of WNT Signaling Pathway) • ATRX (ATRX Chromatin Remodeler) • TSC2 (TSC complex subunit 2) • IGF1R (Insulin-like growth factor 1 receptor) • NOTCH2 (Notch 2) • CREBBP (CREB binding protein) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • SMO (Smoothened Frizzled Class Receptor) • BCOR (BCL6 Corepressor) • ERBB4 (erb-b2 receptor tyrosine kinase 4) • FAT1 (FAT atypical cadherin 1) • KDM6A (Lysine Demethylase 6A) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • PIK3CG (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma) • NOTCH3 (Notch Receptor 3) • ARID1B (AT-Rich Interaction Domain 1B) • EP300 (E1A binding protein p300) • FLT4 (Fms-related tyrosine kinase 4) • IGF1 (Insulin-like growth factor 1) • NSD1 (Nuclear Receptor Binding SET Domain Protein 1) • RAD51D (RAD51 paralog D) • RICTOR (RPTOR Independent Companion Of MTOR Complex 2) • EPHA2 (EPH receptor A2) • BMI1 (BMI1 proto-oncogene, polycomb ring finger) • CASP8 (Caspase 8) • CCND3 (Cyclin D3) • BRD4 (Bromodomain Containing 4) • DDR2 (Discoidin domain receptor 2) • FLCN (Folliculin) • KDM5A (Lysine Demethylase 5A) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • DPYD (Dihydropyrimidine Dehydrogenase) • EPHA5 (EPH Receptor A5) • EPHB1 (EPH Receptor B1) • FGF10 (Fibroblast Growth Factor 10) • FGF23 (Fibroblast Growth Factor 23) • MAP2K4 (Mitogen-Activated Protein Kinase Kinase 4) • SMAD3 (SMAD Family Member 3)
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TP53 mutation • KRAS mutation • BRCA2 mutation • BRCA1 mutation • EGFR mutation • TMB-H • NRAS mutation • PIK3CA mutation • EGFR amplification • ATM mutation • PIK3CA H1047R • STK11 mutation • DNMT3A mutation • PALB2 mutation • POLE mutation • NF1 mutation • NOTCH1 mutation • ASXL1 mutation • CDKN2A deletion • BCL2 overexpression • KEAP1 mutation • SF3B1 mutation • CDKN2A mutation • KMT2D mutation • CDK12 mutation • LRP1B mutation • VHL mutation • PIK3CA amplification • HRAS mutation • APC mutation • ATR mutation • ATRX mutation • CCND1 amplification • PDGFRA mutation • CREBBP mutation • MSH2 mutation • RNF43 mutation • ROS1 mutation • SMAD4 mutation • BCOR mutation • FGFR4 mutation • KDM6A mutation • RAD51D mutation • TSC2 mutation • FAT1 mutation • MYC mutation • ARID1B mutation • NOTCH3 mutation • PMS2 mutation • SMO mutation • IKZF1 mutation • MDM2 mutation • NTRK1 mutation • EP300 mutation • ERBB4 mutation • NSD1 mutation • PIK3CA H1047R + PIK3C2B amplification • PIK3CG mutation • SETD2 mutation • EPHA5 mutation • EPHB1 mutation • ERCC2 mutation • FGF10 amplification • FGF23 mutation • FLCN mutation • HGF mutation • PDGFRB mutation • RAD51 mutation
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cisplatin • Gilotrif (afatinib) • dasatinib • 5-fluorouracil • Halaven (eribulin mesylate)
over1year
Opposing Effects of KDM6A and JDP2 on Glucocorticoid Sensitivity in T-ALL. (PubMed, Blood Adv)
We transplanted and treated ten primary mouse T-lineage acute lymphoblastic leukemias (T-ALLs) initiated by retroviral insertional mutagenesis with the GC dexamethasone (DEX)...Analysis of paired samples from two KDM6A-mutant T-ALL patients in a relapsed pediatric ALL cohort revealed a somatic NR3C1 mutation at relapse in one and markedly elevated JDP2 expression in another. Together, these data implicate JDP2 over-expression as a mechanism of adaptive GC resistance in T-ALL that functionally interacts with KDM6A inactivation.
Journal
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KDM6A (Lysine Demethylase 6A) • JDP2 (Jun Dimerization Protein 2) • NR3C1 (Nuclear Receptor Subfamily 3 Group C Member 1)
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KDM6A mutation • JDP2 overexpression
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dexamethasone
almost2years
BRCA1/2 Reversion Mutations in Patients Treated with Poly ADP-Ribose Polymerase (PARP) Inhibitors or Platinum Agents. (PubMed, Medicina (Kaunas))
These reversion mutations were rare; this may be because some patients may not have had repeat profiling post-treatment. Repeat tumor profiling at times of treatment resistance can help inform therapy selection in the refractory disease setting.
Journal • BRCA Biomarker • PARP Biomarker
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ER (Estrogen receptor) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • KDM6A (Lysine Demethylase 6A)
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BRCA2 mutation • BRCA1 mutation • KDM6A mutation
2years
KDM6A Loss Recruits Tumor-Associated Neutrophils and Promotes Neutrophil Extracellular Trap Formation in Pancreatic Cancer. (PubMed, Cancer Res)
These findings shed light on how KDM6A regulates the tumor immune microenvironment and PDAC progression and suggests that the CXCL1-CXCR2 axis may be a candidate target in PDAC with KDM6A loss. KDM6A loss in pancreatic cancer cells alters the immune microenvironment by increasing CXCL1 secretion and neutrophil recruitment, providing a rationale for targeting the CXCL1-CXCR2 signaling axis in tumors with low KDM6A.
Journal
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KDM6A (Lysine Demethylase 6A) • CXCR2 (Chemokine (C-X-C motif) receptor 2) • CXCL1 (Chemokine (C-X-C motif) ligand 1)
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KDM6A mutation
2years
Opposing Effects of KDM6A and JDP2 on Glucocorticoid Sensitivity in T-ALL (ASH 2022)
In an unbiased in vivo screen to discover GC resistance mechanisms, we transplanted and treated 10 primary mouse T-ALLs initiated by retroviral insertional mutagenesis with the GC dexamethasone (DEX) (Wandler et al., 2020). We also unexpectedly found that KDM6A inactivation sensitizes T-ALL cells to GC treatment and hypothesize that this results in strong selective pressure for the outgrowth of GC-resistant clones due to JDP2 over-expression and other mechanisms. The FDA-approved BCL-2 inhibitor venetoclax and H3K27me3 inhibition are rational therapeutic approaches for potentially overcoming adaptive GC resistance in relapsed patients with KDM6A-mutant T-ALL.
IO biomarker
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KDM6A (Lysine Demethylase 6A) • CASP3 (Caspase 3) • JDP2 (Jun Dimerization Protein 2) • NR3C1 (Nuclear Receptor Subfamily 3 Group C Member 1)
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KDM6A mutation • JDP2 overexpression • KDM6A expression
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Venclexta (venetoclax) • dexamethasone
over2years
Combined Kdm6a and Trp53 deficiency drives the development of squamous cell skin cancer in mice. (PubMed, J Invest Dermatol)
Four of sixteen tumors exhibited deletions in large portions of chromosome 1 involving Ncstn, while another 25% of tumors harbored deletions in chromosome 19 involving Pten, implicating the loss of other tumor suppressors as cooperating events for combined Kdm6a- and Trp53-dependent tumorigenesis. This study suggests that KDM6A acts as an important tumor suppressor for cSCC pathogenesis.
Preclinical • Journal • Tumor Mutational Burden
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TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • PTEN (Phosphatase and tensin homolog) • NOTCH1 (Notch 1) • KDM6A (Lysine Demethylase 6A)
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TP53 mutation • TMB-H • KDM6A mutation
over2years
KDM6A mutation act as a potential immunotherapy biomarker in urothelial carcinoma (ESMO 2022)
We collected 275 patients from IMvigor210, a phase 2 trial evaluated efficacy of atezolizumab in UC...Conclusions Our research revealed that patients with UC harboring KDM6A mutation had a better clinical outcomes of immunotherapy, indicating KDM6A mutation can be regarded as a potential immunotherapy biomarker in UC. Future researches should focus on the validation of the predictive value of KDM6A in prospective trials and more fundamental exploration of its molecular mechanism.
Tumor Mutational Burden • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • KDM6A (Lysine Demethylase 6A)
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TMB-H • KDM6A mutation
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Tecentriq (atezolizumab)
over2years
Molecular Stratification of Medulloblastoma: Clinical Outcomes and Therapeutic Interventions. (PubMed, Anticancer Res)
Recent WHO (2021) guidelines stratified MB into four molecular subgroups with four and eight further subgroups for SHH and non-WNT/non-SHH MB, respectively. In this review, we discuss advancements in genetics, epigenetics, and transcriptomics for better characterization, prognostication, and treatment of MB using precision medicine.
Clinical data • Review • Journal
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TP53 (Tumor protein P53) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • PTCH1 (Patched 1) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • KDM6A (Lysine Demethylase 6A) • CDK6 (Cyclin-dependent kinase 6) • GLI1 (GLI Family Zinc Finger 1) • GFI1 (Growth Factor Independent 1 Transcriptional Repressor) • GLI2 (GLI Family Zinc Finger 2)
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TP53 mutation • MYC amplification • KDM6A mutation • TP53 amplification • CDK6 amplification
almost3years
THE HISTONE DEMETHYLASE KDM6A REGULATES HEMATOPOIETIC STEM AND PROGENITOR CELLS EMERGENCE AND ITS LOSS CAUSES MYELOID-BIASED DIFFERENTIATION IN ZEBRAFISH (EBMT 2022)
 kdm6a is required for HSPCs emergence and lineages differentiation in zebrafish embryos. Our kdm6a-/- zebrafish model will be a helpful tool to understand the process of hematopoiesis.
Epigenetic controller
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RUNX1 (RUNX Family Transcription Factor 1) • KDM6A (Lysine Demethylase 6A) • RAG1 (Recombination Activating 1)
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KDM6A mutation • KDM6A expression
almost3years
Specific genomic alterations and prognostic analysis of perihilar cholangiocarcinoma and distal cholangiocarcinoma. (PubMed, J Gastrointest Oncol)
In this study, we investigated the comprehensive genomic characterizations of CCA patients, identified the significant alterations in each subtype, and identified potential biomarkers for prognosis prediction. These results provide molecular evidence for the heterogeneity of CCA subtypes and evidence for further precision targeted therapy of CCA patients.
Journal • Tumor Mutational Burden
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HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • FGFR2 (Fibroblast growth factor receptor 2) • ARID1A (AT-rich interaction domain 1A) • NF1 (Neurofibromin 1) • TERT (Telomerase Reverse Transcriptase) • MDM2 (E3 ubiquitin protein ligase) • SMAD4 (SMAD family member 4) • KDM6A (Lysine Demethylase 6A) • ARID2 (AT-Rich Interaction Domain 2) • FAT4 (FAT Atypical Cadherin 4) • TCF7L2 (Transcription Factor 7 Like 2) • MAP2K4 (Mitogen-Activated Protein Kinase Kinase 4)
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TP53 mutation • KRAS mutation • PIK3CA mutation • HER-2 mutation • ARID1A mutation • FGFR2 mutation • NF1 mutation • KDM6A mutation • TP53 mutation + KRAS mutation • TERT mutation • MDM2 mutation • TCF7L2 mutation
almost3years
Germline BRCA2, ATM and CHEK2 alterations shape somatic mutation landscapes in prostate cancer. (ASCO-GU 2022)
Biallelic inactivation was frequently observed in PCa patients harboring gATM and gBRCA2 mutations, but not in those with gCHEK2 mutations. gBRCA2-altered patients were enriched for somatic AR (and FOXA1) mutations and were depleted for TMPRSS2-ERG fusions. gATM-altered patients were depleted for somatic TP53 mutations, while gCHEK2-altered patients were enriched for somatic CDK12 mutations.
BRCA Biomarker
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TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • KDM6A (Lysine Demethylase 6A) • ERG (ETS Transcription Factor ERG) • FOXA1 (Forkhead Box A1)
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TP53 mutation • BRCA2 mutation • PIK3CA mutation • ATM mutation • PTEN mutation • CDK12 mutation • CHEK2 mutation • AR mutation • KDM6A mutation • TMPRSS2-ERG fusion • FOXA1 mutation
almost3years
Kdm6a deficiency restricted to mouse hematopoietic cells causes an age- and sex-dependent myelodysplastic syndrome-like phenotype. (PubMed, PLoS One)
Utilizing scRNA-seq, Kdm6a loss was linked to the transcriptional repression of genes that mediate hematopoietic cell fate determination. These data demonstrate that Kdm6a plays an important role in normal hematopoiesis, and that its inactivation may contribute to AML pathogenesis.
Preclinical • Journal
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KDM6A (Lysine Demethylase 6A) • VAV1 (Vav Guanine Nucleotide Exchange Factor 1)
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KDM6A mutation
3years
KDM6 Demethylases Integrate DNA Repair Gene Regulation: Loss of KDM6A Sensitizes AML to PARP Inhibition and Potentiates with BCL2 Blockade (ASH 2021)
In addition, olaparib administration significantly reduced bone marrow engraftment of patient-derived xenografts of KDM6A -mutant primary AML...Using venet responsive isogenic lines we demonstrated that attenuation of KDM6 function increased mitochondrial activity, intracellular ROS levels, de-repressed BCL2 expression, and sensitized AML cells to venetoclax...KDM6s have been implicated in solid tumors, and both PARP and BCL2 inhibitors are being tested in cancer patients, underscoring a wider scope of application. To conclude, KDM6A unfolds to be a central regulator for susceptibility of AML to both PARP and BCL2 inhibition, expanding the possibility to characterize effective combination targeted therapy for AML in clinical settings.
PARP Biomarker • IO biomarker • Epigenetic controller
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FLT3 (Fms-related tyrosine kinase 3) • BCL2 (B-cell CLL/lymphoma 2) • HRD (Homologous Recombination Deficiency) • TET2 (Tet Methylcytosine Dioxygenase 2) • KDM6A (Lysine Demethylase 6A) • BCL2A1 (BCL2 Related Protein A1) • KDM6B (Lysine Demethylase 6B)
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BCL2 expression • KDM6A mutation • BCL2A1 expression • KDM6A expression
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Venclexta (venetoclax) • Lynparza (olaparib)
3years
[VIRTUAL] Genomic Features of Radiation-Associated Muscle-Invasive Bladder Cancer (ASTRO 2021)
In this study, we characterize the mutational profiles and clinical outcomes of radiation-associated bladder cancer. These patients exhibited significantly worse PFS and OS compared to prior series of de novo MIBC. Genomically, these tumors exhibited higher rates of mutation signatures characteristic of impaired DNA damage repair compared to previously unirradiated tumors.
BRCA Biomarker
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TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • MSH6 (MutS homolog 6) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • KDM6A (Lysine Demethylase 6A)
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TP53 mutation • BRCA2 mutation • BRCA1 mutation • MSI-H/dMMR • CHEK2 mutation • FANCA mutation • KDM6A mutation
3years
Genomic Features of Radiation-Associated Muscle-Invasive Bladder Cancer. (PubMed, Int J Radiat Oncol Biol Phys)
In this study, we characterize the mutational profiles and clinical outcomes of radiation-associated bladder cancer. These patients exhibited significantly worse PFS and OS compared to prior series of de novo MIBC. Genomically, these tumors exhibited higher rates of mutation signatures characteristic of impaired DNA damage repair compared to previously unirradiated tumors. These genomic differences suggest that some RA-MIBCs may represent a biologically distinct entity compared to de novo MIBC and may indicate an opportunity for the use and development of novel therapeutic strategies.
Journal • BRCA Biomarker
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TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • MSH6 (MutS homolog 6) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • KDM6A (Lysine Demethylase 6A)
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TP53 mutation • BRCA2 mutation • BRCA1 mutation • MSI-H/dMMR • CHEK2 mutation • FANCA mutation • KDM6A mutation
3years
KDM6A Regulates Cell Plasticity and Pancreatic Cancer Progression by Non-Canonical Activin Pathway. (PubMed, Cell Mol Gastroenterol Hepatol)
Loss of KDM6A accelerates PDAC progression and metastasis, most likely by a non-canonical p38-dependant activin A pathway. KDM6A also promotes pancreatic tissue recovery from pancreatitis. Activin A might be utilized as a therapeutic target for KDM6A-deficient PDACs.
Journal
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • KDM6A (Lysine Demethylase 6A)
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TP53 mutation • KRAS mutation • KDM6A mutation • KRAS mutation + TP53 mutation
over3years
[VIRTUAL] Genomic characterization of Radiation associated Muscle-Invasive Bladder Cancer (AUA 2021)
We characterize mutational features and clinical outcomes of RA-MIBC. These patients exhibited significantly worse PFS and OS compared to primary MIBC. Although these tumors share mutations known to be associated with primary bladder tumors, we identified unique features associated with prior radiation therapy that may represent a biologically distinct entity compared to primary non-radiation associated bladder cancer.
BRCA Biomarker
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TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSH6 (MutS homolog 6) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • KDM6A (Lysine Demethylase 6A)
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TP53 mutation • BRCA2 mutation • BRCA1 mutation • CHEK2 mutation • FANCA mutation • KDM6A mutation
over3years
Significance of KDM6A mutation in bladder cancer immune escape. (PubMed, BMC Cancer)
Overall, we conclude that KDM6A mutation is frequent in BC and promotes tumour immune escape, which may serve as a novel biomarker to predict the immune response.
Journal
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HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • FGFR3 (Fibroblast growth factor receptor 3) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • RB1 (RB Transcriptional Corepressor 1) • ARID1A (AT-rich interaction domain 1A) • MUC16 (Mucin 16, Cell Surface Associated) • KDM6A (Lysine Demethylase 6A) • STAG2 (Stromal Antigen 2) • EP300 (E1A binding protein p300) • CSMD3 (CUB And Sushi Multiple Domains 3)
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TP53 mutation • PIK3CA mutation • ERBB3 mutation • KDM6A mutation • STAG2 mutation • KDM6A expression
over3years
A diffusion-like process accommodates new crypts during clonal expansion in human colonic epithelium. (PubMed, Gastroenterology)
Advantaged gene mutations in KDM6A expand dramatically by crypt fission but not fusion. The crypt diffusion process enables accommodation of the additional crypts up to a threshold value, beyond which polyp growth may occur. The fission rate associated with KRAS mutations offers a potential explanation for KRAS-initiated polyps.
Journal • Tumor Mutational Burden
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KRAS (KRAS proto-oncogene GTPase) • TMB (Tumor Mutational Burden) • KDM6A (Lysine Demethylase 6A)
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KRAS mutation • KDM6A mutation
over3years
Targeted deep sequencing of bladder tumors reveals novel associations between cancer gene mutations and mutational signatures with major risk factors. (PubMed, Clin Cancer Res)
These data quantify the contribution of BC risk factors to mutational burden and suggest different signature enrichments among never, former, and current smokers.
Clinical • Journal • Tumor Mutational Burden
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TMB (Tumor Mutational Burden) • ERCC2 (Excision repair cross-complementation group 2) • KDM6A (Lysine Demethylase 6A)
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KDM6A mutation
almost4years
[VIRTUAL] Tumor mutation burden and immune microenvironment analysis of urothelial carcinoma. (ASCO-GU 2021)
This study provides new insights into the correlation between the TMB and the immune microenvironment in urothelial carcinoma. The result may be a reference to immunotherapy.
Tumor Mutational Burden • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • CD8 (cluster of differentiation 8) • KMT2D (Lysine Methyltransferase 2D) • KDM6A (Lysine Demethylase 6A)
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PD-L1 expression • TP53 mutation • TMB-H • MSI-H/dMMR • KMT2D mutation • KDM6A mutation