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    1. karim2001khoury 19 Feb 2026
      An oncogenic Ezh2 mutation cooperates with particular genetic alterations to induce tumors in mice and redistributes H3K27 trimethylation throughout the genome

      [Paper-level Aggregated] PMCID: PMC4899144

      Evidence Type(s): Oncogenic, Functional, Predictive, Prognostic

      Justification: Oncogenic: The expression of the Ezh2Y641F mutation in mouse B-cells and melanocytes led to the development of high-penetrance lymphoma and melanoma, indicating its role in promoting cancer. Functional: The study demonstrated that Ezh2Y641F exhibits altered enzymatic activity, with decreased mono-methylase activity but increased di- and tri-methylase activity, suggesting a functional change associated with the mutation. Predictive: The presence of the Ezh2Y641F mutation was shown to cooperate with B-RAFV600E in accelerating melanoma formation, indicating its potential to predict tumorigenesis in the context of specific genetic alterations. Prognostic: The study reported that mice expressing Ezh2Y641F had a median survival of one year, suggesting that the mutation may have implications for disease progression and patient outcomes.

      Gene→Variant (gene-first): BRAF(673):B-RAFV600E BRAF(673):B-RafV600E EZH2(2146):Y641F EZH2(2146):Y646 EZH2(2146):tyrosine to phenylalanine EZH2(2146):Y646F

      Genes: BRAF(673) EZH2(2146)

      Variants: B-RAFV600E B-RafV600E Y641F Y646 tyrosine to phenylalanine Y646F

      CIViC paper-level aggregated PMC4899144
    2. karim2001khoury 19 Feb 2026
      Finally, we analyzed the effect of the Ezh2Y641F mutation on the entire genome, focusing on melanoma cell lines. Toward this end, we identified broad H3K27me3 domains in Ezh2+/+ cells across the genome, and then compared

      [Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 23

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the Ezh2Y641F mutation alters the molecular function of the enzyme, specifically its effect on H3K27me3 distribution, indicating a change in biochemical activity. Oncogenic: The context of the study involves analyzing the Ezh2Y641F mutation in melanoma cell lines, suggesting that this somatic variant contributes to tumor development or progression.

      Gene→Variant (gene-first): 2146:Y641F

      Genes: 2146

      Variants: Y641F

      CIViC paragraph-level PMC4899144 Functional Oncogenic
    3. karim2001khoury 19 Feb 2026
      We next analyzed mean normalized H3K27me3 signal around the TSS (+- 5 kb) of genes with a significant change in expression between Ezh2+/+ and Ezh2Y641F/+ cells (Supplementary Table 1 and 2). Genes upregulated in the pre

      [Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 22

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the Ezh2Y641F variant affects the H3K27me3 signal around the transcription start site and gene body, indicating an alteration in molecular function related to gene expression regulation. Oncogenic: The variant Ezh2Y641F is associated with changes in gene expression in cancer cell lines, suggesting its role in tumor development or progression.

      Gene→Variant (gene-first): 2146:Y641F

      Genes: 2146

      Variants: Y641F

      CIViC paragraph-level PMC4899144 Functional Oncogenic
    4. karim2001khoury 19 Feb 2026
      We analyzed the effects of Ezh2Y641F expression on the distribution of H3K27me3 at promoter regions, TSS and gene bodies. Toward that end, we rank-ordered transcripts by level of expression in Ezh2+/+ samples, and averag

      [Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 21

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the Ezh2Y641F variant alters the distribution of H3K27me3, indicating a change in molecular function related to gene expression and chromatin modification.

      Gene→Variant (gene-first): 2146:Y641F

      Genes: 2146

      Variants: Y641F

      CIViC paragraph-level PMC4899144 Functional
    5. karim2001khoury 19 Feb 2026
      To understand the molecular effects of Ezh2 activation in B-cells and melanoma, we performed RNA-seq and H3K27me3 chromatin immunoprecipitation and sequencing (ChIP-seq). As the expression of Ezh2Y641F in young adult mic

      [Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 15

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the Ezh2Y641F variant alters the expression of numerous transcripts in B-cells and melanoma cells, indicating a change in molecular function related to gene expression. Oncogenic: The variant Ezh2Y641F is associated with melanoma cell lines derived from tumors, suggesting its role in tumor development or progression.

      Gene→Variant (gene-first): 2146:Y641F

      Genes: 2146

      Variants: Y641F

      CIViC paragraph-level PMC4899144 Functional Oncogenic
    6. karim2001khoury 19 Feb 2026
      We next assessed the anti-tumor efficacy of EZH2 inhibitors in vivo. We studied lymphoma in CD19CREEzh2Y641F+ mice with autochthonous tumors, and melanoma in immunodeficient mice transplanted with cell lines derived from

      [Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 13

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the anti-tumor efficacy of EZH2 inhibitors and their effects on tumor growth inhibition in Ezh2Y641F/+ tumors, indicating a correlation with treatment response. Oncogenic: The variant Ezh2Y641F is implicated in tumor development, as it is studied in the context of autochthonous tumors in mice, suggesting its role in contributing to tumor progression.

      Gene→Variant (gene-first): 2146:Y641F

      Genes: 2146

      Variants: Y641F

      CIViC paragraph-level PMC4899144 Predictive Oncogenic
    7. karim2001khoury 19 Feb 2026
      Next we investigated whether Ezh2 inhibition could suppress tumor growth in these mice. shRNA-mediated knock-down of Ezh2 in cell lines derived from the mouse melanomas described above resulted in significant growth inhi

      [Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the response of melanoma cell lines with the Y641F variant to various EZH2 inhibitors, indicating a correlation between the variant and sensitivity to treatment. Functional: The passage describes how the Y641F variant affects the potency of the JQEZ5 inhibitor, demonstrating that the variant alters the molecular function of EZH2 in the context of drug response.

      Gene→Variant (gene-first): 2146:Y641F 2146:Y646F

      Genes: 2146

      Variants: Y641F Y646F

      CIViC paragraph-level PMC4899144 Predictive Functional
    8. karim2001khoury 19 Feb 2026
      We performed experiments to address the cooperation of EZH2 mutation with B-RAF but not N-RAS. We observed that the expression of N-RAS and B-RAF is not altered by the presence of the Y641F mutation (data not shown). A m

      [Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 10

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses the oncogenic effects of the B-RAFV600E and Ezh2Y641F mutations in the context of melanoma formation, indicating that these variants contribute to tumor development or progression. Functional: The passage describes how the presence of the Y641F mutation does not alter the expression of certain genes, suggesting that it may affect molecular or biochemical functions related to oncogenic pathways.

      Gene→Variant (gene-first): 673:B-RAFV600E 2146:Y641F

      Genes: 673 2146

      Variants: B-RAFV600E Y641F

      CIViC paragraph-level PMC4899144 Oncogenic Functional
    9. karim2001khoury 19 Feb 2026
      In contrast, melanocyte-specific activation of Ezh2Y641F in the presence of N-RasQ61R did not accelerate melanomagenesis, with or without p16Ink4a loss (Fig. 2d). As B-RAF is thought to be a downstream effector of N-RAS

      [Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 9

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses the role of B-RafV600E and Ezh2Y641F in promoting melanoma, indicating that these variants contribute to tumor development or progression. Functional: The mention of B-Raf as a downstream effector of N-RAS signaling suggests that the variant B-RafV600E alters molecular function in the context of signaling pathways involved in melanoma.

      Gene→Variant (gene-first): 673:B-RafV600E 2146:Y641F

      Genes: 673 2146

      Variants: B-RafV600E Y641F

      CIViC paragraph-level PMC4899144 Oncogenic Functional
    10. karim2001khoury 19 Feb 2026
      In addition to lymphoma, EZH2Y646 mutations are observed in 3% of human melanoma , with focal amplifications of EZH2 noted in 15 of 262 (5.7%) of cases from the Cancer Genome Atlas (TCGA). As B-RAFV600E or N-RASQ61R muta

      [Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage describes how the Ezh2Y641F mutation cooperates with the B-RAFV600E mutation to accelerate tumorigenesis in melanoma, indicating that it contributes to tumor development. Functional: The passage implies that the Ezh2Y641F mutation alters the tumorigenic process in conjunction with B-RAFV600E, suggesting a change in molecular function related to tumor maintenance and formation.

      Gene→Variant (gene-first): 673:B-RAFV600E 673:B-RafV600E 2146:Y641F

      Genes: 673 2146

      Variants: B-RAFV600E B-RafV600E Y641F

      CIViC paragraph-level PMC4899144 Oncogenic Functional
    11. karim2001khoury 19 Feb 2026
      In vitro, EZH2Y641F exhibits decreased H3K27 mono-methylase activity, but increased di- and tri-methylase activity compared to EZH2+/+ , suggesting that transformation may require expression of both wild-type and mutant

      [Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 6

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the EZH2Y641F variant exhibits altered methylase activity, indicating that the variant affects molecular function. Oncogenic: The evidence suggests that the EZH2Y641F mutation contributes to tumor development, as demonstrated by the tumorigenesis observed in mice harboring this mutation.

      Gene→Variant (gene-first): 2146:Y641F 2146:Y646 2146:tyrosine to phenylalanine

      Genes: 2146

      Variants: Y641F Y646 tyrosine to phenylalanine

      CIViC paragraph-level PMC4899144 Functional Oncogenic
    12. karim2001khoury 19 Feb 2026
      To determine whether genetic alterations detected in human B-cell lymphomas cooperate with Ezh2Y641F in tumor formation, we transduced hematopoietic progenitors from CD19CRE/+Ezh2+/+ or CD19CRE/+Ezh2Y641F/+ mice with ret

      [Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses how the Ezh2Y641F variant contributes to tumor formation in B-cell lymphomas, indicating its role in tumor development and progression. Functional: The variant is associated with altered molecular function, specifically in the context of its cooperation with other genetic alterations to influence B-cell transformation and apoptotic resistance.

      Gene→Variant (gene-first): 2146:Y641F

      Genes: 2146

      Variants: Y641F

      CIViC paragraph-level PMC4899144 Oncogenic Functional
    13. karim2001khoury 19 Feb 2026
      To examine the effects of Ezh2Y641F on B-cell malignancy, we longitudinally observed a cohort of littermate CD19CRE/+Ezh2Y641F/+ and CD19CRE/+Ezh2+/+ animals. In contrast to results employing animals expressing Ezh2Y641F

      [Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 4

      Evidence Type(s): Oncogenic, Prognostic

      Justification: Oncogenic: The passage describes how the Ezh2Y641F variant contributes to the development of B-cell lymphoma in mice, indicating its role in tumor progression. Prognostic: The median survival of one year for mice with the Ezh2Y641F variant suggests a correlation with disease outcome, specifically survival, independent of therapy.

      Gene→Variant (gene-first): 2146:Y641F

      Genes: 2146

      Variants: Y641F

      CIViC paragraph-level PMC4899144 Oncogenic Prognostic
    14. karim2001khoury 19 Feb 2026
      We validated expression of the Ezh2Y641F allele by Southern blot, PCR and qRT-PCR (Fig. 1a, Supplementary Fig. 1a-d). In the absence of CRE-mediated recombination, the allele produces a wild-type transcript (Fig. 1a) and

      [Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the Y641F mutation alters the expression of Ezh2 transcripts and leads to a gain-of-function effect, evidenced by the increase in H3K27me3 levels in B-cells, indicating a change in molecular function. Oncogenic: The Y641F mutation is described as equivalent to a common EZH2 missense mutation found in human cancers, suggesting its role in tumor development or progression.

      Gene→Variant (gene-first): 2146:Y641F 2146:Y646F

      Genes: 2146

      Variants: Y641F Y646F

      CIViC paragraph-level PMC4899144 Functional Oncogenic
    15. karim2001khoury 19 Feb 2026
      B-cell lymphoma and melanoma harbor recurrent mutations in the gene encoding the EZH2 histone methyltransferase, but the carcinogenic role of these mutations is unclear. Here we describe a mouse model in which the most c

      [Paragraph-level] PMCID: PMC4899144 Section: ABSTRACT PassageIndex: 1

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage describes how the somatic mutations Y641F and Y646F in the EZH2 gene contribute to tumor development, specifically leading to high-penetrance lymphoma and melanoma in a mouse model. Functional: The variant Ezh2Y641F is shown to alter molecular function by increasing global H3K27 trimethylation and causing a redistribution of this mark, which affects transcription at various loci.

      Gene→Variant (gene-first): 2146:Y641F 2146:Y646F

      Genes: 2146

      Variants: Y641F Y646F

      CIViC paragraph-level PMC4899144 Oncogenic Functional
    16. karim2001khoury 19 Feb 2026
      B-cell lymphoma and melanoma harbor recurrent mutations in the gene encoding the EZH2 histone methyltransferase, but the carcinogenic role of these mutations is unclear. Here we describe a mouse model in which the most c

      [Paragraph-level] PMCID: PMC4899144 Section: ABSTRACT PassageIndex: 1

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage describes how the somatic mutations Y641F and Y646F in the EZH2 gene contribute to tumor development, specifically leading to high-penetrance lymphoma and melanoma in a mouse model. Functional: The variant Ezh2Y641F is shown to alter molecular function by increasing global H3K27 trimethylation and causing a redistribution of this mark, which affects transcription at various loci.

      Gene→Variant (gene-first): 2146:Y641F 2146:Y646F

      Genes: 2146

      Variants: Y641F Y646F

      CIViC paragraph-level PMC4899144 Oncogenic Functional
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    pmc.ncbi.nlm.nih.gov/articles/PMC4899144/pdf/nihms773752.pdf