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    1. karim2001khoury 19 Feb 2026
      Kinome multigenic panel identified novel druggable EPHB4‐V871I somatic variant in high‐risk neuroblastoma

      [Paper-level Aggregated] PMCID: PMC7294133

      Evidence Type(s): Oncogenic, Functional, Prognostic

      Justification: Oncogenic: The variant EPHB4-V871I is associated with increased proliferation, migration, and invasion properties in neuroblastoma cell lines, indicating its role in promoting tumorigenesis. Functional: The study demonstrates that EPHB4-V871I affects cellular functions such as proliferation and migration, and alters the expression of downstream target genes, confirming its functional impact in vitro. Prognostic: Higher EPHB4 expression, correlated with the EPHB4-V871I variant, is associated with advanced disease stages and poor overall survival in neuroblastoma patients.

      Gene→Variant (gene-first): MYCN(4613):A417S EPHB4(2050):V871I ALK(238):F1174L

      Genes: MYCN(4613) EPHB4(2050) ALK(238)

      Variants: A417S V871I F1174L

      CIViC paper-level aggregated PMC7294133
    2. karim2001khoury 19 Feb 2026
      Neuroblastoma (NB) is the most common extracranial neoplasm in children. The overall outcome for high-risk NB patients is still unacceptable, therefore, it is critical to deeply understand molecular mechanisms associated

      [Paragraph-level] PMCID: PMC7294133 Section: ABSTRACT PassageIndex: 2

      Evidence Type(s): Oncogenic, Predictive, Prognostic

      Justification: Oncogenic: The variant V871I in the EPHB4 gene is described as contributing to increased proliferation, migration, and invasion properties in neuroblastoma cell lines, indicating its role in tumor development and progression. Predictive: The passage discusses the use of EPHB4 inhibitors that can rescue the phenotype driven by the variant V871I, suggesting a correlation with response to specific therapies. Prognostic: The passage mentions that higher EPHB4 expression is correlated with stage 4 neuroblastoma and poor overall survival, indicating a relationship between the variant and disease outcome.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Oncogenic Predictive Prognostic
    3. karim2001khoury 19 Feb 2026
      Treatment with TK inhibitors rescues the phenotype induced by EPHB4-V871I in NB cell lines

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage indicates that treatment with TK inhibitors has a positive effect on the phenotype induced by the EPHB4-V871I variant, suggesting a correlation with response to therapy. Oncogenic: The mention of the EPHB4-V871I variant inducing a phenotype in neuroblastoma (NB) cell lines implies that it contributes to tumor development or progression.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Predictive Oncogenic
    4. karim2001khoury 19 Feb 2026
      We then tried to study possible targets of EPHB4. We studied three EPHB4 downstream target genes by analysing the mRNA levels of: VEGF, c-RAF and CDK4 genes by qRt-PCR. All three of these genes showed significantly highe

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 15

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the expression levels of downstream target genes and affects the phosphorylation status of the ERK1-2 pathway, indicating a change in molecular function.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Functional
    5. karim2001khoury 19 Feb 2026
      EPHB4-V871I increases the expression of some target genes and enhance the phosphorylation of ERK1-2 pathway

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 14

      Evidence Type(s): Functional

      Justification: Functional: The variant V871I alters molecular function by increasing the expression of target genes and enhancing the phosphorylation of the ERK1-2 pathway.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Functional
    6. karim2001khoury 19 Feb 2026
      We further analysed the anchorage-independent growth of EPHB4-MUT by colony formation assay in soft agar. EPHB4-V871I showed an increased number of colonies compared with WT and EV in both cell lines (Figure 4B).

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 13

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The variant EPHB4-V871I is associated with increased anchorage-independent growth, indicating its contribution to tumor development or progression as demonstrated by the colony formation assay. Functional: The passage describes the effect of the EPHB4-V871I variant on cellular behavior, specifically its impact on colony formation, which suggests an alteration in molecular or biochemical function.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Oncogenic Functional
    7. karim2001khoury 19 Feb 2026
      We further analysed the migration properties of EPHB4 mutant clone by two-dimensional migration experiments. EPHB4-V871I showed an increased number of migrating cells compared with EV and EPHB4-WT in both cell lines (Fig

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the migration properties of cells, indicating a change in molecular function related to cell behavior.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Functional
    8. karim2001khoury 19 Feb 2026
      The migration potential was firstly assayed by wound-healing experiments demonstrating increased migration properties of EPHB4-V871I compared with both EV and EPHB4-WT in both cell lines (Figure 3C). Indeed, the percenta

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 11

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the migration properties of cells, indicating a change in molecular function related to cell behavior.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Functional
    9. karim2001khoury 19 Feb 2026
      Due to EPHB4 involvement in tumour angiogenesis, growth and metastasis, 21 we speculated on its potential regulation of cellular proliferation, cell migration and anchorage-independent growth in vitro. The proliferation

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 10

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the proliferation rate of cells, indicating a change in molecular or biochemical function. Oncogenic: The increased proliferation rate associated with the EPHB4-V871I variant suggests its contribution to tumor development or progression, as it is linked to cellular behaviors relevant to cancer.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Functional Oncogenic
    10. karim2001khoury 19 Feb 2026
      EPHB4-V871I affects proliferation and migration of NB cell lines

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 9

      Evidence Type(s): Functional

      Justification: Functional: The passage indicates that EPHB4-V871I alters the proliferation and migration of neuroblastoma (NB) cell lines, suggesting a change in molecular or biochemical function.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Functional
    11. karim2001khoury 19 Feb 2026
      In order to select the cell lines to perform the functional characterization of EPHB4-V871I variant, we firstly analysed the expression of EPHB4 in several NB cell lines. We divided our cell lines based on MYCN amplified

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses the functional characterization of the EPHB4-V871I variant, specifically evaluating its expression and confirming that the mutation does not impair EPHB4 expression at the mRNA and protein level.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Functional
    12. karim2001khoury 19 Feb 2026
      The screening of kinome regions in NB cell lines resulted in 11 filtered mutations in eight genes. Here, we detected four additional ALK mutations. Of these, three were F1174L changes, and the other was the R1275Q change

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 5

      Evidence Type(s): None

      Justification: Not enough information in this passage.

      Gene→Variant (gene-first): 238:F1174L 2260:N457K 238:R1275Q

      Genes: 238 2260

      Variants: F1174L N457K R1275Q

      CIViC paragraph-level PMC7294133
    13. karim2001khoury 19 Feb 2026
      Interestingly, we found two mutations in EPHB4 (V871I) and in EphB6 (A417S) genes, both involved in axon guidance pathway. The variant V871I in the kinase domain of EPHB4 showed a high pathogenic score (Figure 1A and Tab

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 4

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses mutations in EPHB4 and EphB6 genes, indicating that the variant V871I is associated with a high pathogenic score, suggesting its contribution to tumor development or progression. Functional: The mention of the variant V871I being located in the kinase domain of EPHB4 implies a potential alteration in molecular or biochemical function related to its role in the axon guidance pathway.

      Gene→Variant (gene-first): 4613:A417S 2050:V871I

      Genes: 4613 2050

      Variants: A417S V871I

      CIViC paragraph-level PMC7294133 Oncogenic Functional
    14. karim2001khoury 19 Feb 2026
      We performed targeted sequencing of TK domains on a total of 45 NB normal-primary tumour matched pairs and 9 NB cell lines. All tumour samples were high-risk patients according to the COG Risk Group Classification System

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage indicates that the variant F1174L is a somatic mutation found in the ALK gene, which is associated with neuroblastoma (NB), suggesting its contribution to tumor development or progression.

      Gene→Variant (gene-first): 238:F1174L

      Genes: 238

      Variants: F1174L

      CIViC paragraph-level PMC7294133 Oncogenic
    16. karim2001khoury 19 Feb 2026
      Treatment with TK inhibitors rescues the phenotype induced by EPHB4-V871I in NB cell lines

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage indicates that treatment with TK inhibitors has a positive effect on the phenotype induced by the EPHB4-V871I variant, suggesting a correlation with response to therapy. Oncogenic: The mention of the EPHB4-V871I variant inducing a phenotype in neuroblastoma (NB) cell lines implies that it contributes to tumor development or progression.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Predictive Oncogenic
    17. karim2001khoury 19 Feb 2026
      We then tried to study possible targets of EPHB4. We studied three EPHB4 downstream target genes by analysing the mRNA levels of: VEGF, c-RAF and CDK4 genes by qRt-PCR. All three of these genes showed significantly highe

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 15

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the expression levels of downstream target genes and affects the phosphorylation status of the ERK1-2 pathway, indicating a change in molecular function.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Functional
    18. karim2001khoury 19 Feb 2026
      EPHB4-V871I increases the expression of some target genes and enhance the phosphorylation of ERK1-2 pathway

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 14

      Evidence Type(s): Functional

      Justification: Functional: The variant V871I alters molecular function by increasing the expression of target genes and enhancing the phosphorylation of the ERK1-2 pathway.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Functional
    19. karim2001khoury 19 Feb 2026
      We further analysed the anchorage-independent growth of EPHB4-MUT by colony formation assay in soft agar. EPHB4-V871I showed an increased number of colonies compared with WT and EV in both cell lines (Figure 4B).

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 13

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The variant EPHB4-V871I is associated with increased anchorage-independent growth, indicating its contribution to tumor development or progression as demonstrated by the colony formation assay. Functional: The passage describes the effect of the EPHB4-V871I variant on cellular behavior, specifically its impact on colony formation, which suggests an alteration in molecular or biochemical function.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Oncogenic Functional
    20. karim2001khoury 19 Feb 2026
      We further analysed the migration properties of EPHB4 mutant clone by two-dimensional migration experiments. EPHB4-V871I showed an increased number of migrating cells compared with EV and EPHB4-WT in both cell lines (Fig

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the migration properties of cells, indicating a change in molecular function related to cell behavior.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Functional
    21. karim2001khoury 19 Feb 2026
      The migration potential was firstly assayed by wound-healing experiments demonstrating increased migration properties of EPHB4-V871I compared with both EV and EPHB4-WT in both cell lines (Figure 3C). Indeed, the percenta

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 11

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the migration properties of cells, indicating a change in molecular function related to cell behavior.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Functional
    22. karim2001khoury 19 Feb 2026
      Due to EPHB4 involvement in tumour angiogenesis, growth and metastasis, 21 we speculated on its potential regulation of cellular proliferation, cell migration and anchorage-independent growth in vitro. The proliferation

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 10

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the proliferation rate of cells, indicating a change in molecular or biochemical function. Oncogenic: The increased proliferation rate associated with the EPHB4-V871I variant suggests its contribution to tumor development or progression, as it is linked to cellular behaviors relevant to cancer.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Functional Oncogenic
    23. karim2001khoury 19 Feb 2026
      EPHB4-V871I affects proliferation and migration of NB cell lines

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 9

      Evidence Type(s): Functional

      Justification: Functional: The passage indicates that EPHB4-V871I alters the proliferation and migration of neuroblastoma (NB) cell lines, suggesting a change in molecular or biochemical function.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Functional
    24. karim2001khoury 19 Feb 2026
      In order to select the cell lines to perform the functional characterization of EPHB4-V871I variant, we firstly analysed the expression of EPHB4 in several NB cell lines. We divided our cell lines based on MYCN amplified

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses the functional characterization of the EPHB4-V871I variant, specifically evaluating its expression and confirming that the mutation does not impair EPHB4 expression at the mRNA and protein level.

      Gene→Variant (gene-first): 2050:V871I

      Genes: 2050

      Variants: V871I

      CIViC paragraph-level PMC7294133 Functional
    25. karim2001khoury 19 Feb 2026
      The screening of kinome regions in NB cell lines resulted in 11 filtered mutations in eight genes. Here, we detected four additional ALK mutations. Of these, three were F1174L changes, and the other was the R1275Q change

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 5

      Evidence Type(s): None

      Justification: Not enough information in this passage.

      Gene→Variant (gene-first): 238:F1174L 2260:N457K 238:R1275Q

      Genes: 238 2260

      Variants: F1174L N457K R1275Q

      CIViC paragraph-level PMC7294133
    26. karim2001khoury 19 Feb 2026
      Interestingly, we found two mutations in EPHB4 (V871I) and in EphB6 (A417S) genes, both involved in axon guidance pathway. The variant V871I in the kinase domain of EPHB4 showed a high pathogenic score (Figure 1A and Tab

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 4

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses mutations in EPHB4 and EphB6 genes, indicating that the variant V871I is associated with a high pathogenic score, suggesting its contribution to tumor development or progression. Functional: The mention of the variant V871I being located in the kinase domain of EPHB4 implies a potential alteration in molecular or biochemical function related to its role in the axon guidance pathway.

      Gene→Variant (gene-first): 4613:A417S 2050:V871I

      Genes: 4613 2050

      Variants: A417S V871I

      CIViC paragraph-level PMC7294133 Oncogenic Functional
    27. karim2001khoury 19 Feb 2026
      We performed targeted sequencing of TK domains on a total of 45 NB normal-primary tumour matched pairs and 9 NB cell lines. All tumour samples were high-risk patients according to the COG Risk Group Classification System

      [Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage indicates that the variant F1174L is a somatic mutation found in the ALK gene, which is associated with neuroblastoma (NB), suggesting its contribution to tumor development or progression.

      Gene→Variant (gene-first): 238:F1174L

      Genes: 238

      Variants: F1174L

      CIViC paragraph-level PMC7294133 Oncogenic
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    pmc.ncbi.nlm.nih.gov/articles/PMC7294133/pdf/JCMM-24-6459.pdf