[Paper-level Aggregated] PMCID: PMC2848976

Evidence Type(s): Functional

Summary: Mutation: BRAFV600E | Summary: The BRAFV600E mutation is associated with changes in the phosphorylation state of ERK1/2, high enzymatic activity, alterations in gene expression, and activation of downstream ERK targets. It also affects intracellular signaling pathways, leading to differential activation and downregulation of FOS and JUNB in response to treatment, and is linked to changes in phospho-FAK activation and ERK1/2 phosphorylation. Additionally, it is associated with a reduction in cell motility in response to PLX4032, indicating a functional impact on melanoma cell behavior.

Evidence Type: Functional Mutation: BRAFV600K | Summary: The BRAFV600K mutation is associated with high enzymatic activity, indicating that it alters molecular function.

Evidence Type: Functional Mutation: R89L | Summary: The R89L mutation in RAF1 does not bind Ras-GTP, indicating a change in molecular function, as it was activated by PLX4032 similarly to wild-type RAF1.

Evidence Type: Functional Mutation: Q61L | Summary: The Q61L mutation in NRAS may alter molecular or biochemical function, as it is implicated in the activation of signaling pathways in melanoma cells. The presence of NRAS Q61L mutant primary melanoma cells shows altered cellular behaviors, indicating a change in molecular function.

Gene→Variant (gene-first): BRAF(673):BRAFV600E BRAF(673):BRAFV600K JUNB(3726):R89L NRAS(4893):Q61L

Genes: BRAF(673) JUNB(3726) NRAS(4893)

Variants: BRAFV600E BRAFV600K R89L Q61L

[Paper-level Aggregated] PMCID: PMC2848976

Evidence Type(s): Oncogenic

Summary: Mutation: V600E | Summary: The V600E mutation in BRAF contributes to tumor development and progression in melanoma, supporting its classification as an oncogenic variant. It is associated with altered activation of early response genes and impacts ERK1/2 functional activation, as well as changes in cell adhesion and migration in melanoma cells.

Evidence Type: Oncogenic Mutation: BRAFV600E | Summary: The BRAFV600E mutation contributes to tumor development or progression in melanoma, as evidenced by its presence in specific melanoma cell lines and its impact on ERK signaling. It is associated with non-detectable activity in certain cell lines, altered activation of early response genes, and changes in cell adhesion and migration. Additionally, it is linked to a lack of activation of IL8 in response to PLX4032 treatment and shows differential responses to PLX4032 compared to BRAFWT melanoma cells.

Evidence Type: Oncogenic Mutation: BRAFV600K | Summary: The BRAFV600K mutation contributes to tumor development or progression in melanoma, as indicated by its role in melanoma cells and is associated with non-detectable activity in certain cell lines.

Evidence Type: Oncogenic Mutation: Q61L | Summary: The NRAS Q61L mutation is associated with tumor development or progression in melanoma, as indicated by its presence in primary melanoma cells. It is linked to advanced lesions and altered cell behavior, contributing to tumor progression, and may alter molecular or biochemical function by activating signaling pathways in melanoma cells.

Gene→Variant (gene-first): BRAF(673):V600E BRAF(673):BRAFV600E BRAF(673):BRAFV600K NRAS(4893):Q61L

Genes: BRAF(673) NRAS(4893)

Variants: V600E BRAFV600E BRAFV600K Q61L

[Paper-level Aggregated] PMCID: PMC2848976

Evidence Type(s): Predictive

Summary: Mutation: V600E | Summary: The V600E mutation in BRAF is associated with sensitivity to the therapy PLX4032, indicating a predictive relationship between the mutation and treatment response.

Evidence Type: Predictive Mutation: BRAFV600E | Summary: The BRAFV600E mutation correlates with the response to the therapy PLX4032, as it abolishes ERK1/2 activating phosphorylation in melanoma cells, and is associated with a response to the drug, indicating its predictive value for therapy sensitivity. Additionally, the presence of the BRAFV600E mutation correlates with the lack of response to PLX4032 treatment, suggesting its predictive value for therapy resistance.

Evidence Type: Predictive Mutation: BRAFV600K | Summary: The BRAFV600K mutation correlates with the response to PLX4032, showing a similar pattern of ERK1/2 phosphorylation in response to the drug.

Evidence Type: Predictive Mutation: BRAFV600E/K | Summary: BRAFV600E/K is targeted for therapy with the specific inhibitor PLX4032, indicating a correlation with treatment response.

Evidence Type: Predictive Mutation: Q61L | Summary: PLX4032 increased the rate of proliferation in NRAS Q61L mutant primary melanoma cells, suggesting a correlation with treatment response.

Gene→Variant (gene-first): BRAF(673):V600E BRAF(673):BRAFV600E BRAF(673):BRAFV600K NA:BRAFV600E/K NRAS(4893):Q61L

Genes: BRAF(673) NA NRAS(4893)

Variants: V600E BRAFV600E BRAFV600K BRAFV600E/K Q61L

[Paragraph-level] PMCID: PMC2848976 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic, Functional

Summary: Evidence Type: Predictive | Mutation: BRAFV600E/K | Summary: BRAFV600E/K is targeted for therapy with the specific inhibitor PLX4032, indicating a correlation with treatment response. Evidence Type: Oncogenic | Mutation: BRAFV600E/K | Summary: BRAFV600E/K is described as a mutationally active tumor-specific kinase in melanomas, contributing to tumor development. Evidence Type: Functional | Mutation: Q61L | Summary: The presence of NRAS Q61L mutant primary melanoma cells shows altered cellular behaviors, indicating a change in molecular function. Evidence Type: Predictive | Mutation: Q61L | Summary: PLX4032 increased the rate of proliferation in NRAS Q61L mutant primary melanoma cells, suggesting a correlation with treatment response. Evidence Type: Oncogenic | Mutation: Q61L | Summary: The Q61L mutation in NRAS is associated with advanced lesions and altered cell behavior, contributing to tumor progression.

Gene→Variant (gene-first): 673:BRAFV600E 4893:Q61L 673:V600E/K

Genes: 673 4893

Variants: BRAFV600E Q61L V600E/K

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 24

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: BRAFV600E | Summary: The BRAFV600E mutation is associated with a reduction in cell motility in response to PLX4032, indicating a functional impact on the behavior of melanoma cells. Evidence Type: Oncogenic | Mutation: BRAFV600E | Summary: The BRAFV600E mutation contributes to tumor development or progression, as evidenced by its differential response to PLX4032 compared to BRAFWT melanoma cells.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 23

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: BRAFV600E | Summary: The BRAFV600E mutation is associated with changes in cell adhesion and migration in melanoma cells, indicating its role in tumor development and progression. Evidence Type: Functional | Mutation: BRAFV600E | Summary: The BRAFV600E mutation alters molecular function, as evidenced by the changes in phospho-FAK activation and ERK1/2 phosphorylation in response to treatment.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 21

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: Q61L | Summary: The NRAS Q61L mutation is associated with tumor development or progression in melanoma, as indicated by its presence in primary melanoma cells. Evidence Type: Functional | Mutation: Q61L | Summary: The Q61L mutation in NRAS may alter molecular or biochemical function, as it is implicated in the activation of signaling pathways in melanoma cells.

Gene→Variant (gene-first): 4893:Q61L

Genes: 4893

Variants: Q61L

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 18

Evidence Type(s): Oncogenic, Predictive

Summary: Evidence Type: Oncogenic | Mutation: BRAFV600E | Summary: The BRAFV600E mutation is associated with the lack of activation of IL8 in response to PLX4032 treatment, indicating its role in tumor development or progression. Evidence Type: Predictive | Mutation: BRAFV600E | Summary: The presence of the BRAFV600E mutation correlates with the lack of response to PLX4032 treatment, suggesting its predictive value for therapy resistance.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 17

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: BRAFV600E | Summary: The BRAFV600E mutation is associated with altered activation of early response genes and contributes to tumor development or progression as indicated by its impact on ERK1/2 functional activation in melanoma cells. Evidence Type: Functional | Mutation: BRAFV600E | Summary: The BRAFV600E mutation alters the molecular function of signaling pathways, as evidenced by the differential activation and downregulation of FOS and JUNB in response to treatment in mutant versus wild-type melanoma cells.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: BRAFV600E | Summary: The BRAFV600E mutation is associated with changes in gene expression and activation of downstream ERK targets, indicating an alteration in molecular function related to cellular responses to therapy.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: R89L | Summary: The R89L mutation in RAF1 does not bind Ras-GTP, indicating a change in molecular function, as it was activated by PLX4032 similarly to wild-type RAF1.

Gene→Variant (gene-first): 3726:R89L

Genes: 3726

Variants: R89L

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: BRAFV600E | Summary: The BRAFV600E mutation is associated with non-detectable activity in certain cell lines, indicating its role in tumor development or progression. Evidence Type: Oncogenic | Mutation: BRAFV600K | Summary: The BRAFV600K mutation is associated with non-detectable activity in certain cell lines, indicating its role in tumor development or progression.

Gene→Variant (gene-first): 673:BRAFV600E 673:BRAFV600K

Genes: 673

Variants: BRAFV600E BRAFV600K

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: BRAFV600E | Summary: The BRAFV600E mutation is associated with high enzymatic activity, indicating that it alters molecular function. Evidence Type: Functional | Mutation: BRAFV600K | Summary: The BRAFV600K mutation is associated with high enzymatic activity, indicating that it alters molecular function.

Gene→Variant (gene-first): 673:BRAFV600E 673:BRAFV600K

Genes: 673

Variants: BRAFV600E BRAFV600K

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: BRAFV600E | Summary: The passage discusses the effects of the BRAFV600E mutation on intracellular signaling pathways, indicating that it alters the molecular function related to the response to PLX4032 treatment.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Oncogenic

Summary: Evidence Type: Predictive | Mutation: BRAFV600E | Summary: The BRAFV600E mutation is associated with a response to the drug PLX4032, indicating its predictive value for therapy sensitivity. Evidence Type: Oncogenic | Mutation: BRAFV600E | Summary: The BRAFV600E mutation contributes to tumor development or progression, as evidenced by its role in melanoma cells.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: BRAFV600E | Summary: The BRAFV600E mutation is associated with changes in the phosphorylation state of ERK1/2, indicating an alteration in molecular function related to signaling pathways in melanoma cells. Evidence Type: Oncogenic | Mutation: BRAFV600E | Summary: The BRAFV600E mutation contributes to tumor development or progression in melanoma, as evidenced by its presence in specific melanoma cell lines and its impact on ERK signaling.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Oncogenic

Summary: Evidence Type: Predictive | Mutation: BRAFV600E | Summary: The BRAFV600E mutation correlates with the response to the therapy PLX4032, as it abolishes ERK1/2 activating phosphorylation in melanoma cells. Evidence Type: Predictive | Mutation: BRAFV600K | Summary: The BRAFV600K mutation also correlates with the response to PLX4032, as it shows a similar pattern of ERK1/2 phosphorylation in response to the drug. Evidence Type: Oncogenic | Mutation: BRAFV600E | Summary: The BRAFV600E mutation contributes to tumor development or progression, as indicated by its role in melanoma cells. Evidence Type: Oncogenic | Mutation: BRAFV600K | Summary: The BRAFV600K mutation contributes to tumor development or progression, as indicated by its role in melanoma cells.

Gene→Variant (gene-first): 673:BRAFV600K 673:V600E/K

Genes: 673

Variants: BRAFV600K V600E/K

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Summary: Evidence Type: Predictive | Mutation: V600E | Summary: The V600E mutation in BRAF is associated with sensitivity to the therapy PLX4032, indicating a predictive relationship between the mutation and treatment response. Evidence Type: Oncogenic | Mutation: V600E | Summary: The V600E mutation in BRAF contributes to tumor development and progression in melanoma, supporting its classification as an oncogenic variant.

Gene→Variant (gene-first): 673:V600E

Genes: 673

Variants: V600E

[Paper-level Aggregated] PMCID: PMC2848976

Evidence Type(s): Predictive, Oncogenic, Functional

Justification: Predictive: The study demonstrates that the presence of BRAF mutations, specifically BRAFV600E/K, predicts sensitivity to the drug PLX4032, as evidenced by the significantly lower IC50 values in BRAF mutant melanoma cell strains compared to BRAF wild-type cells. Oncogenic: The BRAFV600E/K mutations are described as frequent mutationally active tumor-specific kinases in melanomas, indicating their role in driving oncogenesis in these tumors. Functional: The study explores the functional effects of PLX4032 on ERK1/2 phosphorylation and downstream signaling pathways, demonstrating how BRAF mutations influence cellular responses to the drug.

Gene→Variant (gene-first): BRAF(673):BRAFV600E BRAF(673):BRAFV600K NRAS(4893):Q61L BRAF(673):V600E/K JUNB(3726):R89L BRAF(673):V600E

Genes: BRAF(673) NRAS(4893) JUNB(3726)

Variants: BRAFV600E BRAFV600K Q61L V600E/K R89L V600E

[Paragraph-level] PMCID: PMC2848976 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic, Functional

Justification: Predictive: The passage discusses how BRAFV600E/K is targeted for therapy with the specific inhibitor PLX4032, indicating a correlation with treatment response. Oncogenic: BRAFV600E/K is described as a mutationally active tumor-specific kinase in melanomas, suggesting its role in tumor development or progression. Functional: The passage mentions that PLX4032 alters the activity of ERK1/2 in BRAFV600E/K cells, indicating a change in molecular function related to the variant.

Gene→Variant (gene-first): 673:BRAFV600E 4893:Q61L 673:V600E/K

Genes: 673 4893

Variants: BRAFV600E Q61L V600E/K

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 24

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how activated FAK has a functional impact on BRAFWT melanoma cells, specifically noting changes in colony formation and cell motility in response to PLX4032, indicating alterations in molecular or biochemical function. Oncogenic: The mention of BRAFWT and BRAFV600E in the context of melanoma cells suggests that these variants are involved in tumor behavior, particularly in how they respond to treatment and their migratory capabilities, indicating a role in tumor development or progression.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 23

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the effects of PLX4032 on melanoma cells, indicating a difference in response between BRAFWT and BRAFV600E cells, which suggests a correlation with treatment response. Oncogenic: The mention of BRAFV600E in the context of advanced melanoma cells implies that this somatic variant contributes to tumor development or progression, as it is associated with specific cellular behaviors in the study.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 21

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 4893:Q61L

Genes: 4893

Variants: Q61L

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 18

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of melanoma cells to the therapy PLX4032, indicating that the BRAFV600E variant is associated with a lack of activation of certain proteins in response to treatment, which suggests a predictive relationship regarding therapy response. Oncogenic: The mention of BRAFV600E in the context of melanoma cells implies its role as a somatic variant contributing to tumor development or progression, as it is a well-known oncogenic mutation in melanoma.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 17

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of BRAFV600E cells to PLX4032, indicating a correlation with treatment response. Oncogenic: The mention of BRAFV600E in the context of downregulation of FOS and the activation of ERK1/2 suggests that this somatic variant contributes to tumor behavior and progression.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 16

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the cellular responses to PLX4032 therapy and mentions the activation of downstream ERK targets in relation to the BRAFV600E variant, indicating a correlation with treatment response. Oncogenic: The BRAFV600E variant is implicated in the inhibition of p90RSK activation in melanoma cells, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the R89L variant of RAF1 alters its ability to bind Ras-GTP and its activation in response to PLX4032, indicating a change in molecular function. Oncogenic: The R89L variant is described in the context of its activation and role in signaling pathways, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 3726:R89L

Genes: 3726

Variants: R89L

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the activity of RAF1 kinase in relation to BRAFV600E and BRAFV600K variants, indicating that these variants alter the molecular function of RAF1, as evidenced by the observed kinase activity levels. Oncogenic: The mention of BRAFV600E and BRAFV600K in the context of non-detectable activity and their relationship to RAF1 activity suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 673:BRAFV600E 673:BRAFV600K

Genes: 673

Variants: BRAFV600E BRAFV600K

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses the enzymatic activity of BRAF variants (BRAFV600E and BRAFV600K) and how their activity is altered by treatment with PLX4032, indicating a change in molecular function. Predictive: The mention of treatment with PLX4032 and its effect on the activity of BRAF variants suggests a correlation with response to therapy, indicating predictive evidence.

Gene→Variant (gene-first): 673:BRAFV600E 673:BRAFV600K

Genes: 673

Variants: BRAFV600E BRAFV600K

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 8

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of melanoma cells with the BRAFV600E variant to the drug PLX4032, indicating a correlation with treatment sensitivity. Oncogenic: The BRAFV600E variant is implicated in the context of melanoma cells, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses changes in the phosphorylation state of ERK1/2 in response to treatment, indicating that the BRAFV600E variant alters the molecular function of these proteins in melanoma cells. Oncogenic: The mention of the BRAFV600E variant in the context of melanoma cells suggests that it contributes to tumor development or progression, as it is associated with changes in signaling pathways relevant to cancer.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the effects of PLX4032 on BRAFV600E/K melanoma cells, indicating a correlation between the variant and response to the therapy, specifically in terms of ERK1/2 phosphorylation. Oncogenic: The mention of BRAFV600E/K in the context of melanoma cells suggests that these somatic variants contribute to tumor development or progression, as they are associated with the activation of the RAF-MEK-ERK pathway in cancer.

Gene→Variant (gene-first): 673:BRAFV600K 673:V600E/K

Genes: 673

Variants: BRAFV600K V600E/K

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the sensitivity of BRAF mutant melanoma cell strains, including those with the V600E mutation, to the drug PLX4032, indicating a correlation between the variant and response to therapy. Oncogenic: The V600E variant is mentioned in the context of BRAF mutations in melanoma cells, suggesting its role in tumor development or progression as part of the BRAF mutation profile.

Gene→Variant (gene-first): 673:V600E

Genes: 673

Variants: V600E