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    1. karim2001khoury 19 Feb 2026
      Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer

      [Paper-level Aggregated] PMCID: PMC8285406

      Evidence Type(s): Oncogenic, Predictive, Prognostic

      Justification: Oncogenic: The text describes several FGFR mutations, including N546K, K656E, S249C, and others, as oncogenic mutations that exhibit significant transforming activities in various cancers, indicating their role in tumorigenesis. Predictive: The evidence indicates that specific FGFR mutations, such as N549D/K and K650M/N, show different sensitivities to FGFR inhibitors, suggesting that these variants can predict the response to targeted therapies. Prognostic: The text mentions that patients with FGFR mutations and fusions had a higher overall response rate to FGFR TKIs compared to those with amplifications, indicating that these mutations may serve as prognostic markers for treatment outcomes.

      Gene→Variant (gene-first): PIK3CA(5290):E542K PIK3CA(5290):E545K PIK3CA(5290):H1047R KRAS(3845):G12V FGFR1(2260):N546K FGFR2(2263):N549D/K FGFR3(2261):G370C FGFR3(2261):G380E/R FGFR3(2261):K650E/M FGFR2(2263):K659E FGFR2(2263):N549H FGFR3(2261):R248C FGFR3(2261):S249C TACC1(6867):S342F FGFR3(2261):S371C FGFR2(2263):W290C FGFR3(2261):Y373C FGFR3(2261):K650E FGFR3(2261):K650M FGFR3(2261):K650N FGFR2(2263):N549K FGFR2(2263):K656 FGFR2(2263):K656E/M FGFR2(2263):N549 FGFR2(2263):N549D/H FGFR1(2260):K656E FGFR2(2263):S252W FGFR2(2263):V550L FGFR4(2264):N535K EGFR(1956):R248H

      Genes: PIK3CA(5290) KRAS(3845) FGFR1(2260) FGFR2(2263) FGFR3(2261) TACC1(6867) FGFR4(2264) EGFR(1956)

      Variants: E542K E545K H1047R G12V N546K N549D/K G370C G380E/R K650E/M K659E N549H R248C S249C S342F S371C W290C Y373C K650E K650M K650N N549K K656 K656E/M N549 N549D/H K656E S252W V550L N535K R248H

      CIViC paper-level aggregated PMC8285406
    2. karim2001khoury 19 Feb 2026
      We also investigated whether drug efficacy is dependent on the FGFR variants in patients. For this purpose, we retrospectively collected variant information and drug efficacy data related to FGFR inhibitors in 399 cases

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 22

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the correlation between the FGFR3 S249C variant and the response to treatment with FGFR TKIs, indicating that patients with this mutation exhibited partial or complete responses, which aligns with predictive evidence. Oncogenic: The FGFR3 S249C variant is described as the most frequent mutation of FGFR3, suggesting its role in tumor development or progression, which supports its classification as oncogenic.

      Gene→Variant (gene-first): 2261:S249C

      Genes: 2261

      Variants: S249C

      CIViC paragraph-level PMC8285406 Predictive Oncogenic
    3. karim2001khoury 19 Feb 2026
      Furthermore, the existence of concurrent mutations between FGFRs and the genes involved in different pathways, such as PIK3CA, PTEN, AKT1/2/3, and MAP2K1 was investigated. Indeed, concurrent mutations with PIK3CA were fr

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 21

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage indicates that the mutations E545K, E542K, and H1047R are described as "oncogenic mutations," suggesting they contribute to tumor development or progression.

      Gene→Variant (gene-first): 5290:E542K 5290:E545K 5290:H1047R

      Genes: 5290

      Variants: E542K E545K H1047R

      CIViC paragraph-level PMC8285406 Oncogenic
    4. karim2001khoury 19 Feb 2026
      More than 400 types of FGFR compound mutations were observed in the COSMIC database, and 34 types of those were reported in more than two samples (Fig. 7a). The most frequent compound mutation is the combination of S249C

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 20

      Evidence Type(s): Oncogenic, Predictive

      Justification: Oncogenic: The passage discusses the transforming activities of FGFR3 S249C compound mutations, indicating that these mutations contribute to tumor development or progression as demonstrated by their evaluation in 3T3 and Ba/F3 cells. Predictive: The passage mentions the sensitivity to E7090 and erdafitinib in relation to the mutations, indicating a correlation with treatment response, which aligns with predictive evidence.

      Gene→Variant (gene-first): 2261:K650E 2261:K650M 2261:S249C 2261:Y373C

      Genes: 2261

      Variants: K650E K650M S249C Y373C

      CIViC paragraph-level PMC8285406 Oncogenic Predictive
    5. karim2001khoury 19 Feb 2026
      Next, we measured the effectiveness of E7090 and erdafitinib in vivo. Mouse 3T3 fibroblasts expressing FGFR1 N546K, FGFR2 N549K, FGFR3 R248C, FGFR3 K650M, or FGFR3 K650N were injected into nude mice that were subsequentl

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the effectiveness of E7090 and erdafitinib in treating tumors with specific variants, indicating a correlation between the variants and the response to these therapies. Oncogenic: The variants are described in the context of tumor growth and response to treatment, suggesting that they contribute to tumor development or progression.

      Gene→Variant (gene-first): 2261:K650M 2261:K650N 2260:N546K 2263:N549K 2261:R248C

      Genes: 2261 2260 2263

      Variants: K650M K650N N546K N549K R248C

      CIViC paragraph-level PMC8285406 Predictive Oncogenic
    6. karim2001khoury 19 Feb 2026
      Inhibition of FGFRs and downstream signaling pathways by FGFR TKIs was evaluated through immunoblot analyses (Fig. 3c). While phosphorylation of FGFR3 K650M was suppressed by E7090 at 100 nM, that of FGFR3 K650N was decr

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 14

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the response of FGFR3 variants K650M and K650N to FGFR TKIs, indicating their sensitivity to specific therapies, which aligns with predictive evidence. Functional: The passage describes the alteration of phosphorylation status of the FGFR3 variants K650M and K650N in response to treatment, indicating a change in molecular function due to the variants.

      Gene→Variant (gene-first): 2261:K650M 2261:K650N

      Genes: 2261

      Variants: K650M K650N

      CIViC paragraph-level PMC8285406 Predictive Functional
    7. karim2001khoury 19 Feb 2026
      Hierarchical clustering analysis was conducted to evaluate the similarity of FGFR inhibitors and FGFR variants using drug sensitivity data of Fig. 4 (Supplementary Fig. 11). FGFR variants were classified into four cluste

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 13

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the sensitivity and resistance of FGFR variants, including N546K and N549D/K, to FGFR inhibitors, indicating a correlation with response to therapy. Oncogenic: The passage mentions that KRAS G12V is part of a cluster composed mainly of oncogenic variants, suggesting its role in tumor development or progression.

      Gene→Variant (gene-first): 3845:G12V 2260:N546K 2263:N549D/K

      Genes: 3845 2260 2263

      Variants: G12V N546K N549D/K

      CIViC paragraph-level PMC8285406 Predictive Oncogenic
    8. karim2001khoury 19 Feb 2026
      To validate the results of the pooled assay, the respective variants to which drug sensitivity was different among TKIs were further analyzed. Interestingly, in the evaluation with the MANO method, different missense var

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Predictive

      Justification: Predictive: The passage discusses how different missense variants at specific amino acid positions in FGFR2 and FGFR3 correlate with varying drug sensitivities to FGFR inhibitors, indicating a relationship between the variants and treatment response.

      Gene→Variant (gene-first): 2263:K656 2263:K656E/M 2263:N549 2263:N549D/H

      Genes: 2263

      Variants: K656 K656E/M N549 N549D/H

      CIViC paragraph-level PMC8285406 Predictive
    9. karim2001khoury 19 Feb 2026
      The drug sensitivity of transformed FGFR variants was also assessed through the MANO method. The mixture of 3T3 cells expressing different types of FGFR variants were treated with eight different targeted drugs, and drug

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 11

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the drug sensitivity of FGFR variants in response to various targeted therapies, indicating that certain variants are sensitive or resistant to specific inhibitors, which aligns with predictive evidence. Oncogenic: The context of transformed FGFR variants suggests that these somatic mutations contribute to tumor development or progression, particularly as they are assessed for their response to targeted therapies.

      Gene→Variant (gene-first): 2264:N535K 2260:N546K 2263:N549D/K 2263:V550L

      Genes: 2264 2260 2263

      Variants: N535K N546K N549D/K V550L

      CIViC paragraph-level PMC8285406 Predictive Oncogenic
    10. karim2001khoury 19 Feb 2026
      The mRNA expression levels were similar among variants in previous studies using the MANO method. We evaluated the mRNA and protein expression of several FGFR3 variants using real-time PCR and western blotting. While a s

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 9

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the evaluation of mRNA and protein expression levels of the R248H variant, indicating that it alters protein expression compared to oncogenic variants, which relates to its molecular function. Oncogenic: The passage implies that the R248H variant is classified as a non-oncogenic variant, contrasting it with oncogenic variants, suggesting its role in tumor development or progression is not supported.

      Gene→Variant (gene-first): 1956:R248H

      Genes: 1956

      Variants: R248H

      CIViC paragraph-level PMC8285406 Functional Oncogenic
    11. karim2001khoury 19 Feb 2026
      Thus, we utilized the MANO method to compare the number of 3T3 cells expressing each FGFR variant between Day 3 and Day 18 in the assessment of the transforming potential (Fig. 2 and Supplementary Fig. 3). In parallel wi

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage discusses the transforming potential of various FGFR variants, indicating that certain mutations contribute to tumor development or progression, as evidenced by their significant transforming activities in assays.

      Gene→Variant (gene-first): 2261:G370C 2261:G380E/R 2261:K650E/M 2263:K659E 2263:N549H 2261:R248C 2261:S249C 6867:S342F 2261:S371C 2263:W290C 2261:Y373C

      Genes: 2261 2263 6867

      Variants: G370C G380E/R K650E/M K659E N549H R248C S249C S342F S371C W290C Y373C

      CIViC paragraph-level PMC8285406 Oncogenic
    12. karim2001khoury 19 Feb 2026
      FGFRs are highly conserved transmembrane receptor tyrosine kinases, comprised of an extracellular domain with three Ig-like domains, followed by a transmembrane domain and a tyrosine kinase domain (Fig. 1a). Firstly, the

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The V550L mutation in FGFR4 is mentioned in the context of rhabdomyosarcoma, suggesting its contribution to tumor development.

      Gene→Variant (gene-first): 2260:K656E 2260:N546K 2261:S249C 2263:S252W 2263:V550L

      Genes: 2260 2261 2263

      Variants: K656E N546K S249C S252W V550L

      CIViC paragraph-level PMC8285406 Oncogenic
    13. karim2001khoury 19 Feb 2026
      We also investigated whether drug efficacy is dependent on the FGFR variants in patients. For this purpose, we retrospectively collected variant information and drug efficacy data related to FGFR inhibitors in 399 cases

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 22

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the correlation between the FGFR3 S249C variant and the response to treatment with FGFR TKIs, indicating that patients with this mutation exhibited partial or complete responses, which aligns with predictive evidence. Oncogenic: The FGFR3 S249C variant is described as the most frequent mutation of FGFR3, suggesting its role in tumor development or progression, which supports its classification as oncogenic.

      Gene→Variant (gene-first): 2261:S249C

      Genes: 2261

      Variants: S249C

      CIViC paragraph-level PMC8285406 Predictive Oncogenic
    14. karim2001khoury 19 Feb 2026
      Furthermore, the existence of concurrent mutations between FGFRs and the genes involved in different pathways, such as PIK3CA, PTEN, AKT1/2/3, and MAP2K1 was investigated. Indeed, concurrent mutations with PIK3CA were fr

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 21

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage indicates that the mutations E545K, E542K, and H1047R are described as "oncogenic mutations," suggesting they contribute to tumor development or progression.

      Gene→Variant (gene-first): 5290:E542K 5290:E545K 5290:H1047R

      Genes: 5290

      Variants: E542K E545K H1047R

      CIViC paragraph-level PMC8285406 Oncogenic
    15. karim2001khoury 19 Feb 2026
      More than 400 types of FGFR compound mutations were observed in the COSMIC database, and 34 types of those were reported in more than two samples (Fig. 7a). The most frequent compound mutation is the combination of S249C

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 20

      Evidence Type(s): Oncogenic, Predictive

      Justification: Oncogenic: The passage discusses the transforming activities of FGFR3 S249C compound mutations, indicating that these mutations contribute to tumor development or progression as demonstrated by their evaluation in 3T3 and Ba/F3 cells. Predictive: The passage mentions the sensitivity to E7090 and erdafitinib in relation to the mutations, indicating a correlation with treatment response, which aligns with predictive evidence.

      Gene→Variant (gene-first): 2261:K650E 2261:K650M 2261:S249C 2261:Y373C

      Genes: 2261

      Variants: K650E K650M S249C Y373C

      CIViC paragraph-level PMC8285406 Oncogenic Predictive
    16. karim2001khoury 19 Feb 2026
      Next, we measured the effectiveness of E7090 and erdafitinib in vivo. Mouse 3T3 fibroblasts expressing FGFR1 N546K, FGFR2 N549K, FGFR3 R248C, FGFR3 K650M, or FGFR3 K650N were injected into nude mice that were subsequentl

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the effectiveness of E7090 and erdafitinib in treating tumors with specific variants, indicating a correlation between the variants and the response to these therapies. Oncogenic: The variants are described in the context of tumor growth and response to treatment, suggesting that they contribute to tumor development or progression.

      Gene→Variant (gene-first): 2261:K650M 2261:K650N 2260:N546K 2263:N549K 2261:R248C

      Genes: 2261 2260 2263

      Variants: K650M K650N N546K N549K R248C

      CIViC paragraph-level PMC8285406 Predictive Oncogenic
    17. karim2001khoury 19 Feb 2026
      Inhibition of FGFRs and downstream signaling pathways by FGFR TKIs was evaluated through immunoblot analyses (Fig. 3c). While phosphorylation of FGFR3 K650M was suppressed by E7090 at 100 nM, that of FGFR3 K650N was decr

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 14

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the response of FGFR3 variants K650M and K650N to FGFR TKIs, indicating their sensitivity to specific therapies, which aligns with predictive evidence. Functional: The passage describes the alteration of phosphorylation status of the FGFR3 variants K650M and K650N in response to treatment, indicating a change in molecular function due to the variants.

      Gene→Variant (gene-first): 2261:K650M 2261:K650N

      Genes: 2261

      Variants: K650M K650N

      CIViC paragraph-level PMC8285406 Predictive Functional
    18. karim2001khoury 19 Feb 2026
      Hierarchical clustering analysis was conducted to evaluate the similarity of FGFR inhibitors and FGFR variants using drug sensitivity data of Fig. 4 (Supplementary Fig. 11). FGFR variants were classified into four cluste

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 13

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the sensitivity and resistance of FGFR variants, including N546K and N549D/K, to FGFR inhibitors, indicating a correlation with response to therapy. Oncogenic: The passage mentions that KRAS G12V is part of a cluster composed mainly of oncogenic variants, suggesting its role in tumor development or progression.

      Gene→Variant (gene-first): 3845:G12V 2260:N546K 2263:N549D/K

      Genes: 3845 2260 2263

      Variants: G12V N546K N549D/K

      CIViC paragraph-level PMC8285406 Predictive Oncogenic
    19. karim2001khoury 19 Feb 2026
      To validate the results of the pooled assay, the respective variants to which drug sensitivity was different among TKIs were further analyzed. Interestingly, in the evaluation with the MANO method, different missense var

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Predictive

      Justification: Predictive: The passage discusses how different missense variants at specific amino acid positions in FGFR2 and FGFR3 correlate with varying drug sensitivities to FGFR inhibitors, indicating a relationship between the variants and treatment response.

      Gene→Variant (gene-first): 2263:K656 2263:K656E/M 2263:N549 2263:N549D/H

      Genes: 2263

      Variants: K656 K656E/M N549 N549D/H

      CIViC paragraph-level PMC8285406 Predictive
    20. karim2001khoury 19 Feb 2026
      The drug sensitivity of transformed FGFR variants was also assessed through the MANO method. The mixture of 3T3 cells expressing different types of FGFR variants were treated with eight different targeted drugs, and drug

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 11

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the drug sensitivity of FGFR variants in response to various targeted therapies, indicating that certain variants are sensitive or resistant to specific inhibitors, which aligns with predictive evidence. Oncogenic: The context of transformed FGFR variants suggests that these somatic mutations contribute to tumor development or progression, particularly as they are assessed for their response to targeted therapies.

      Gene→Variant (gene-first): 2264:N535K 2260:N546K 2263:N549D/K 2263:V550L

      Genes: 2264 2260 2263

      Variants: N535K N546K N549D/K V550L

      CIViC paragraph-level PMC8285406 Predictive Oncogenic
    21. karim2001khoury 19 Feb 2026
      The mRNA expression levels were similar among variants in previous studies using the MANO method. We evaluated the mRNA and protein expression of several FGFR3 variants using real-time PCR and western blotting. While a s

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 9

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the evaluation of mRNA and protein expression levels of the R248H variant, indicating that it alters protein expression compared to oncogenic variants, which relates to its molecular function. Oncogenic: The passage implies that the R248H variant is classified as a non-oncogenic variant, contrasting it with oncogenic variants, suggesting its role in tumor development or progression is not supported.

      Gene→Variant (gene-first): 1956:R248H

      Genes: 1956

      Variants: R248H

      CIViC paragraph-level PMC8285406 Functional Oncogenic
    22. karim2001khoury 19 Feb 2026
      Thus, we utilized the MANO method to compare the number of 3T3 cells expressing each FGFR variant between Day 3 and Day 18 in the assessment of the transforming potential (Fig. 2 and Supplementary Fig. 3). In parallel wi

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage discusses the transforming potential of various FGFR variants, indicating that certain mutations contribute to tumor development or progression, as evidenced by their significant transforming activities in assays.

      Gene→Variant (gene-first): 2261:G370C 2261:G380E/R 2261:K650E/M 2263:K659E 2263:N549H 2261:R248C 2261:S249C 6867:S342F 2261:S371C 2263:W290C 2261:Y373C

      Genes: 2261 2263 6867

      Variants: G370C G380E/R K650E/M K659E N549H R248C S249C S342F S371C W290C Y373C

      CIViC paragraph-level PMC8285406 Oncogenic
    23. karim2001khoury 19 Feb 2026
      FGFRs are highly conserved transmembrane receptor tyrosine kinases, comprised of an extracellular domain with three Ig-like domains, followed by a transmembrane domain and a tyrosine kinase domain (Fig. 1a). Firstly, the

      [Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The V550L mutation in FGFR4 is mentioned in the context of rhabdomyosarcoma, suggesting its contribution to tumor development.

      Gene→Variant (gene-first): 2260:K656E 2260:N546K 2261:S249C 2263:S252W 2263:V550L

      Genes: 2260 2261 2263

      Variants: K656E N546K S249C S252W V550L

      CIViC paragraph-level PMC8285406 Oncogenic
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    pmc.ncbi.nlm.nih.gov/articles/PMC8285406/pdf/41698_2021_Article_204.pdf