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    1. karim2001khoury 19 Feb 2026
      Epidermal Growth Factor Receptor Activation in Glioblastoma through Novel Missense Mutations in the Extracellular Domain

      [Paper-level Aggregated] PMCID: PMC1702556

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

      Justification: Oncogenic: The presence of identical missense mutations in multiple patient samples and their oncogenicity in transformation assays suggest that these mutants play a role in gliomagenesis. Predictive: The data indicate that EGFR missense mutants sensitize transformed cells to EGFR kinase inhibitors, suggesting their potential as predictive biomarkers for response to therapy. Diagnostic: The identification of specific EGFR missense mutations in glioblastoma samples supports their use as diagnostic markers for this type of cancer. Prognostic: The association of certain EGFR mutations with clinical responses to EGFR kinase inhibitors implies that these mutations may have prognostic significance in glioblastoma treatment outcomes.

      Gene→Variant (gene-first): EGFR(1956):A289 EGFR(1956):A289D EGFR(1956):A289T EGFR(1956):E330K EGFR(1956):L861Q EGFR(1956):R108 EGFR(1956):R324L EGFR(1956):A289V EGFR(1956):G598V EGFR(1956):R108K EGFR(1956):T263P EGFR(1956):L858R EGFR(1956):T790M

      Genes: EGFR(1956)

      Variants: A289 A289D A289T E330K L861Q R108 R324L A289V G598V R108K T263P L858R T790M

      CIViC paper-level aggregated PMC1702556
    2. karim2001khoury 19 Feb 2026
      We recently reported the results of a glioblastoma clinical trial with EGFR kinase inhibitors which associated clinical responses to the coexpression of EGFRvIII and PTEN. To investigate whether clinical responses might

      [Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 17

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the association of the R108K variant with clinical responses to EGFR kinase inhibitors, indicating a correlation with treatment response. Oncogenic: The R108K variant is identified in gliomas, suggesting its potential role in tumor development or progression, particularly in the context of EGFR amplification.

      Gene→Variant (gene-first): 1956:R108K

      Genes: 1956

      Variants: R108K

      CIViC paragraph-level PMC1702556 Predictive Oncogenic
    3. karim2001khoury 19 Feb 2026
      The presence of identical missense mutations in multiple patient samples and their oncogenicity in standard transformation assays suggest that these mutants play a role in gliomagenesis. It also raises the question wheth

      [Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses how the presence of EGFR missense mutants, including L858R and L861Q, may sensitize transformed cells to EGFR kinase inhibitors, indicating a correlation with treatment response. Oncogenic: The identical missense mutations are described as having oncogenicity and playing a role in gliomagenesis, suggesting that these somatic variants contribute to tumor development.

      Gene→Variant (gene-first): 1956:L858R 1956:L861Q 1956:T790M

      Genes: 1956

      Variants: L858R L861Q T790M

      CIViC paragraph-level PMC1702556 Predictive Oncogenic
    4. karim2001khoury 19 Feb 2026
      We also expressed selected EGFR mutants (R108K, T263P, A289V, G598V, L861Q) in murine hematopoietic cells (Ba/F3 cells) which do not express any EGFR family members but otherwise retain functional properties of the EGF-s

      [Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 14

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the EGFR mutants (R108K, T263P, A289V, G598V, L861Q) alter the molecular function of the EGF-signaling pathway, specifically showing increased tyrosine phosphorylation and differences in receptor downregulation in response to EGF stimulation.

      Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:R108K 1956:T263P

      Genes: 1956

      Variants: A289V G598V L861Q R108K T263P

      CIViC paragraph-level PMC1702556 Functional
    5. karim2001khoury 19 Feb 2026
      Signal transduction through EGFR is determined by its basal catalytic activity, receptor activation by ligand, and signal termination through intracellular compartmentalization of the receptor-ligand complex, receptor de

      [Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 13

      Evidence Type(s): Functional

      Justification: Functional: The examination of other EGFR missense mutants (T263P, G598V, L861Q) also shows an increase in phosphotyrosine content, suggesting that these variants similarly affect the molecular function of the receptor.

      Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:T263P

      Genes: 1956

      Variants: A289V G598V L861Q T263P

      CIViC paragraph-level PMC1702556 Functional
    6. karim2001khoury 19 Feb 2026
      To further analyze the oncogenic potential of the EGFR mutants, NIH-3T3 subclones stably expressing the same missense mutant receptors (encoding R108K, T263P, A289V, G598V, and L861Q) were inoculated subcutaneously into

      [Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 11

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage describes how NIH-3T3 cells expressing the EGFR missense mutants (R108K, T263P, A289V, G598V, and L861Q) produced large tumors in mice, indicating that these variants contribute to tumor development.

      Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:R108K 1956:T263P

      Genes: 1956

      Variants: A289V G598V L861Q R108K T263P

      CIViC paragraph-level PMC1702556 Oncogenic
    7. karim2001khoury 19 Feb 2026
      To test the oncogenicity of the glioma-related EGFR missense mutations, we transduced NIH-3T3 fibroblasts with retroviruses encoding either wild-type EGFR or selected EGFR missense mutants (encoding R108K, T263P, A289V,

      [Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 10

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage discusses the oncogenicity of EGFR missense mutations, indicating that the expression of these variants (R108K, T263P, A289V, G598V, and L861Q) in NIH-3T3 cells leads to anchorage-independent colony formation, a hallmark of tumorigenic behavior.

      Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:R108K 1956:T263P

      Genes: 1956

      Variants: A289V G598V L861Q R108K T263P

      CIViC paragraph-level PMC1702556 Oncogenic
    8. karim2001khoury 19 Feb 2026
      To define which fraction of the EGFR pool represented the mutant allele in gliomas with EGFR missense mutations, we employed a PCR-cloning strategy previously used by our laboratories for mutation detection in clinical s

      [Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Diagnostic, Oncogenic

      Justification: Diagnostic: The passage discusses the prevalence of specific EGFR missense mutations (R108K, T263P, A289V, and G598V) in gliomas, indicating their association with the disease and their representation in the receptor pool, which supports their use in defining or classifying the disease. Oncogenic: The mention of EGFR missense mutations in the context of gliomas suggests that these somatic variants contribute to tumor development or progression, as they are associated with the receptor pool in tumor samples.

      Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:R108K 1956:T263P

      Genes: 1956

      Variants: A289V G598V R108K T263P

      CIViC paragraph-level PMC1702556 Diagnostic Oncogenic
    9. karim2001khoury 19 Feb 2026
      In all, we identified EGFR missense mutations in 14.4% (19/132) of glioblastomas, 12.5% (1/8) of glioblastoma cell lines, and none (0/11) in lower-grade gliomas. Only one tumor sample harbored a missense mutation in the

      [Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 4

      Evidence Type(s): Diagnostic, Oncogenic, Predisposing

      Justification: Diagnostic: The passage discusses the identification of EGFR missense mutations in glioblastomas and their association with the disease, indicating that these mutations can be used to classify or define the tumor type. Oncogenic: The passage mentions that the identified EGFR mutations contribute to tumor development in glioblastomas, particularly noting the presence of somatic mutations in the tumor samples. Predisposing: The passage specifies that one of the mutations (E330K) was identified as germline, indicating it confers inherited risk for developing disease.

      Gene→Variant (gene-first): 1956:A289 1956:A289D 1956:A289T 1956:E330K 1956:L861Q 1956:R108 1956:R324L

      Genes: 1956

      Variants: A289 A289D A289T E330K L861Q R108 R324L

      CIViC paragraph-level PMC1702556 Diagnostic Oncogenic Predisposing
    10. karim2001khoury 19 Feb 2026
      We recently reported the results of a glioblastoma clinical trial with EGFR kinase inhibitors which associated clinical responses to the coexpression of EGFRvIII and PTEN. To investigate whether clinical responses might

      [Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 17

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the association of the R108K variant with clinical responses to EGFR kinase inhibitors, indicating a correlation with treatment response. Oncogenic: The R108K variant is identified in gliomas, suggesting its potential role in tumor development or progression, particularly in the context of EGFR amplification.

      Gene→Variant (gene-first): 1956:R108K

      Genes: 1956

      Variants: R108K

      CIViC paragraph-level PMC1702556 Predictive Oncogenic
    11. karim2001khoury 19 Feb 2026
      The presence of identical missense mutations in multiple patient samples and their oncogenicity in standard transformation assays suggest that these mutants play a role in gliomagenesis. It also raises the question wheth

      [Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses how the presence of EGFR missense mutants, including L858R and L861Q, may sensitize transformed cells to EGFR kinase inhibitors, indicating a correlation with treatment response. Oncogenic: The identical missense mutations are described as having oncogenicity and playing a role in gliomagenesis, suggesting that these somatic variants contribute to tumor development.

      Gene→Variant (gene-first): 1956:L858R 1956:L861Q 1956:T790M

      Genes: 1956

      Variants: L858R L861Q T790M

      CIViC paragraph-level PMC1702556 Predictive Oncogenic
    12. karim2001khoury 19 Feb 2026
      We also expressed selected EGFR mutants (R108K, T263P, A289V, G598V, L861Q) in murine hematopoietic cells (Ba/F3 cells) which do not express any EGFR family members but otherwise retain functional properties of the EGF-s

      [Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 14

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the EGFR mutants (R108K, T263P, A289V, G598V, L861Q) alter the molecular function of the EGF-signaling pathway, specifically showing increased tyrosine phosphorylation and differences in receptor downregulation in response to EGF stimulation.

      Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:R108K 1956:T263P

      Genes: 1956

      Variants: A289V G598V L861Q R108K T263P

      CIViC paragraph-level PMC1702556 Functional
    13. karim2001khoury 19 Feb 2026
      Signal transduction through EGFR is determined by its basal catalytic activity, receptor activation by ligand, and signal termination through intracellular compartmentalization of the receptor-ligand complex, receptor de

      [Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 13

      Evidence Type(s): Functional

      Justification: Functional: The examination of other EGFR missense mutants (T263P, G598V, L861Q) also shows an increase in phosphotyrosine content, suggesting that these variants similarly affect the molecular function of the receptor.

      Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:T263P

      Genes: 1956

      Variants: A289V G598V L861Q T263P

      CIViC paragraph-level PMC1702556 Functional
    14. karim2001khoury 19 Feb 2026
      To further analyze the oncogenic potential of the EGFR mutants, NIH-3T3 subclones stably expressing the same missense mutant receptors (encoding R108K, T263P, A289V, G598V, and L861Q) were inoculated subcutaneously into

      [Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 11

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage describes how NIH-3T3 cells expressing the EGFR missense mutants (R108K, T263P, A289V, G598V, and L861Q) produced large tumors in mice, indicating that these variants contribute to tumor development.

      Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:R108K 1956:T263P

      Genes: 1956

      Variants: A289V G598V L861Q R108K T263P

      CIViC paragraph-level PMC1702556 Oncogenic
    15. karim2001khoury 19 Feb 2026
      To test the oncogenicity of the glioma-related EGFR missense mutations, we transduced NIH-3T3 fibroblasts with retroviruses encoding either wild-type EGFR or selected EGFR missense mutants (encoding R108K, T263P, A289V,

      [Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 10

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage discusses the oncogenicity of EGFR missense mutations, indicating that the expression of these variants (R108K, T263P, A289V, G598V, and L861Q) in NIH-3T3 cells leads to anchorage-independent colony formation, a hallmark of tumorigenic behavior.

      Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:R108K 1956:T263P

      Genes: 1956

      Variants: A289V G598V L861Q R108K T263P

      CIViC paragraph-level PMC1702556 Oncogenic
    16. karim2001khoury 19 Feb 2026
      To define which fraction of the EGFR pool represented the mutant allele in gliomas with EGFR missense mutations, we employed a PCR-cloning strategy previously used by our laboratories for mutation detection in clinical s

      [Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Diagnostic, Oncogenic

      Justification: Diagnostic: The passage discusses the prevalence of specific EGFR missense mutations (R108K, T263P, A289V, and G598V) in gliomas, indicating their association with the disease and their representation in the receptor pool, which supports their use in defining or classifying the disease. Oncogenic: The mention of EGFR missense mutations in the context of gliomas suggests that these somatic variants contribute to tumor development or progression, as they are associated with the receptor pool in tumor samples.

      Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:R108K 1956:T263P

      Genes: 1956

      Variants: A289V G598V R108K T263P

      CIViC paragraph-level PMC1702556 Diagnostic Oncogenic
    17. karim2001khoury 19 Feb 2026
      In all, we identified EGFR missense mutations in 14.4% (19/132) of glioblastomas, 12.5% (1/8) of glioblastoma cell lines, and none (0/11) in lower-grade gliomas. Only one tumor sample harbored a missense mutation in the

      [Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 4

      Evidence Type(s): Diagnostic, Oncogenic, Predisposing

      Justification: Diagnostic: The passage discusses the identification of EGFR missense mutations in glioblastomas and their association with the disease, indicating that these mutations can be used to classify or define the tumor type. Oncogenic: The passage mentions that the identified EGFR mutations contribute to tumor development in glioblastomas, particularly noting the presence of somatic mutations in the tumor samples. Predisposing: The passage specifies that one of the mutations (E330K) was identified as germline, indicating it confers inherited risk for developing disease.

      Gene→Variant (gene-first): 1956:A289 1956:A289D 1956:A289T 1956:E330K 1956:L861Q 1956:R108 1956:R324L

      Genes: 1956

      Variants: A289 A289D A289T E330K L861Q R108 R324L

      CIViC paragraph-level PMC1702556 Diagnostic Oncogenic Predisposing
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    pmc.ncbi.nlm.nih.gov/articles/PMC1702556/pdf/pmed.0030485.pdf