[Paper-level Aggregated] PMCID: PMC4234187

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

Justification: Oncogenic: The introduction of the C118S mutation into the Kras gene was shown to affect tumorigenesis, specifically leading to fewer lung tumors in Kras+/C118S and KrasC118S/C118S mice when treated with the carcinogen urethane, indicating a role in oncogenic processes. Functional: The study demonstrated that the C118S mutation alters the function of the Kras protein, as it specifically blocks redox-dependent reactions that lead to Ras activation, impacting downstream signaling pathways such as the MAPK pathway. Predictive: The presence of the C118S mutation was associated with a reduced tumor burden and a shift towards smaller tumors in mice, suggesting that this mutation can predict a lower likelihood of tumor development in response to carcinogenic exposure. Prognostic: The findings indicate that mice with the C118S mutation have a different tumorigenic outcome compared to those with wild-type Kras, which could be used to prognosticate the progression and severity of lung tumors in a carcinogen-induced model.

Gene→Variant (gene-first): NOS2(4843):C118 NOS2(4843):C118S KRAS(3845):G13D NRAS(4893):Q61L NOS2(4843):G353 transversion to C NOS2(4843):G353>C NOS2(4843):cysteine 118 KRAS(3845):G12D NOS3(4846):S1177D KRAS(3845):Q61R/L NRAS(4893):Q61R

Genes: NOS2(4843) KRAS(3845) NRAS(4893) NOS3(4846)

Variants: C118 C118S G13D Q61L G353 transversion to C G353>C cysteine 118 G12D S1177D Q61R/L Q61R

[Paragraph-level] PMCID: PMC4234187 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the introduction of a C118S mutation into the Kras allele and its effect on tumorigenesis, indicating that this somatic variant contributes to tumor development or progression. Functional: The passage describes how the thiol residue of cysteine 118 is involved in redox-dependent reactions that lead to Ras activation, suggesting that the C118S mutation alters molecular function related to protein activity.

Gene→Variant (gene-first): 4843:C118 4843:C118S 4843:cysteine 118

Genes: 4843

Variants: C118 C118S cysteine 118

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 16

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the behavior of Kras mutations, specifically KrasC118S and KrasG13D, in the context of transformation and signaling, indicating their role in tumor development and progression. Functional: The analysis of P-Erk1/2 levels upon EGF treatment suggests that the KrasC118S variant alters molecular function related to signaling pathways, as evidenced by the immunoblotting results.

Gene→Variant (gene-first): 4843:C118 4843:C118S 3845:G13D 4893:Q61L

Genes: 4843 3845 4893

Variants: C118 C118S G13D Q61L

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 15

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the identification of oncogenic mutations, specifically Q61R/L, in the context of tumor development in Kras+/C118S mice, indicating that these variants contribute to tumor progression. Functional: The mention of the C118S variant in the context of its allelic origin and mutation status suggests an alteration in molecular function related to the Kras gene, which is relevant to its role in oncogenesis.

Gene→Variant (gene-first): 4843:C118S 4893:Q61R 3845:Q61R/L

Genes: 4843 4893 3845

Variants: C118S Q61R Q61R/L

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 13

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the KrasG12D allele as promoting lung tumorigenesis, indicating its role in tumor development. Functional: The passage describes the C118S mutation's effect on the tumorigenic activity of the oncogenic Kras allele and its interaction with the non-oncogenic allele, suggesting a change in molecular function related to tumor suppression.

Gene→Variant (gene-first): 4843:C118S 3845:G12D

Genes: 4843 3845

Variants: C118S G12D

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage indicates that the variants G12D and C118S are involved in similar tumorigenesis, suggesting that they contribute to tumor development or progression.

Gene→Variant (gene-first): 4843:C118S 3845:G12D

Genes: 4843 3845

Variants: C118S G12D

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the impact of the KrasC118S variant on tumor progression and its association with different tumor types, indicating that this somatic variant contributes to tumor development or progression. Functional: The analysis shows that the KrasC118S variant is associated with reduced P-Akt signaling, suggesting that it alters molecular function related to signaling pathways involved in tumor biology.

Gene→Variant (gene-first): 4843:C118S

Genes: 4843

Variants: C118S

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the KrasC118S variant contributes to tumor development by resulting in fewer tumors and smaller average tumor sizes in mice, indicating its role in tumor progression. Functional: The presence of the KrasC118S allele is shown to alter the tumor characteristics, specifically leading to a shift towards smaller tumors, which suggests an alteration in molecular or biochemical function related to tumor development.

Gene→Variant (gene-first): 4843:C118S

Genes: 4843

Variants: C118S

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the KrasC118S mutation in the context of its role in carcinogenesis and tumor development, particularly in relation to urethane-induced lung tumors characterized by oncogenic Q61R/L mutations in Kras. Functional: The passage implies that the KrasC118S mutation alters the molecular behavior of Kras in the context of tumorigenesis, as it is assessed for its impact on carcinogenesis and tumor development.

Gene→Variant (gene-first): 4843:C118S 3845:Q61R/L

Genes: 4843 3845

Variants: C118S Q61R/L

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic, Prognostic

Justification: Oncogenic: The passage discusses the KrasC118S variant in the context of its role in mouse models, indicating that it does not lead to significant developmental or physiological defects, which suggests its involvement in tumor development or progression. Prognostic: The passage mentions the median lifespan of KrasC118S/C118S mice compared to Kras+/+ mice, indicating a potential correlation with disease outcome, although the difference was not statistically significant.

Gene→Variant (gene-first): 4843:C118S

Genes: 4843

Variants: C118S

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 6

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 4843:C118S

Genes: 4843

Variants: C118S

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the C118S mutation affects the ability of eNOS to stimulate the MAPK pathway and provides evidence of altered molecular function through immunoblot analysis of protein levels and activity. Oncogenic: The passage indicates that the C118S mutation is important for carcinogen-induced lung tumorigenesis, suggesting that it contributes to tumor development or progression.

Gene→Variant (gene-first): 4843:C118S 4843:G353>C 4846:S1177D

Genes: 4843 4846

Variants: C118S G353>C S1177D

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the C118S mutation specifically blocks redox-dependent reactions that lead to Ras activation, indicating an alteration in molecular function. Oncogenic: The context of the study involves investigating the effect of the C118S mutation on Ras function during tumorigenesis, suggesting that this somatic variant contributes to tumor development or progression.

Gene→Variant (gene-first): 4843:C118 4843:C118S 4843:G353 transversion to C 4843:G353>C

Genes: 4843

Variants: C118 C118S G353 transversion to C G353>C

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 16

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the behavior of Kras mutations, specifically KrasC118S and KrasG13D, in the context of transformation and signaling, indicating their role in tumor development and progression. Functional: The analysis of P-Erk1/2 levels upon EGF treatment suggests that the KrasC118S variant alters molecular function related to signaling pathways, as evidenced by the immunoblotting results.

Gene→Variant (gene-first): 4843:C118 4843:C118S 3845:G13D 4893:Q61L

Genes: 4843 3845 4893

Variants: C118 C118S G13D Q61L

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 15

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the identification of oncogenic mutations, specifically Q61R/L, in the context of tumor development in Kras+/C118S mice, indicating that these variants contribute to tumor progression. Functional: The mention of the C118S variant in the context of its allelic origin and mutation status suggests an alteration in molecular function related to the Kras gene, which is relevant to its role in oncogenesis.

Gene→Variant (gene-first): 4843:C118S 4893:Q61R 3845:Q61R/L

Genes: 4843 4893 3845

Variants: C118S Q61R Q61R/L

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 13

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the KrasG12D allele as promoting lung tumorigenesis, indicating its role in tumor development. Functional: The passage describes the C118S mutation's effect on the tumorigenic activity of the oncogenic Kras allele and its interaction with the non-oncogenic allele, suggesting a change in molecular function related to tumor suppression.

Gene→Variant (gene-first): 4843:C118S 3845:G12D

Genes: 4843 3845

Variants: C118S G12D

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage indicates that the variants G12D and C118S are involved in similar tumorigenesis, suggesting that they contribute to tumor development or progression.

Gene→Variant (gene-first): 4843:C118S 3845:G12D

Genes: 4843 3845

Variants: C118S G12D

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the impact of the KrasC118S variant on tumor progression and its association with different tumor types, indicating that this somatic variant contributes to tumor development or progression. Functional: The analysis shows that the KrasC118S variant is associated with reduced P-Akt signaling, suggesting that it alters molecular function related to signaling pathways involved in tumor biology.

Gene→Variant (gene-first): 4843:C118S

Genes: 4843

Variants: C118S

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the KrasC118S variant contributes to tumor development by resulting in fewer tumors and smaller average tumor sizes in mice, indicating its role in tumor progression. Functional: The presence of the KrasC118S allele is shown to alter the tumor characteristics, specifically leading to a shift towards smaller tumors, which suggests an alteration in molecular or biochemical function related to tumor development.

Gene→Variant (gene-first): 4843:C118S

Genes: 4843

Variants: C118S

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the KrasC118S mutation in the context of its role in carcinogenesis and tumor development, particularly in relation to urethane-induced lung tumors characterized by oncogenic Q61R/L mutations in Kras. Functional: The passage implies that the KrasC118S mutation alters the molecular behavior of Kras in the context of tumorigenesis, as it is assessed for its impact on carcinogenesis and tumor development.

Gene→Variant (gene-first): 4843:C118S 3845:Q61R/L

Genes: 4843 3845

Variants: C118S Q61R/L

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic, Prognostic

Justification: Oncogenic: The passage discusses the KrasC118S variant in the context of its role in mouse models, indicating that it does not lead to significant developmental or physiological defects, which suggests its involvement in tumor development or progression. Prognostic: The passage mentions the median lifespan of KrasC118S/C118S mice compared to Kras+/+ mice, indicating a potential correlation with disease outcome, although the difference was not statistically significant.

Gene→Variant (gene-first): 4843:C118S

Genes: 4843

Variants: C118S

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 6

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 4843:C118S

Genes: 4843

Variants: C118S

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the C118S mutation affects the ability of eNOS to stimulate the MAPK pathway and provides evidence of altered molecular function through immunoblot analysis of protein levels and activity. Oncogenic: The passage indicates that the C118S mutation is important for carcinogen-induced lung tumorigenesis, suggesting that it contributes to tumor development or progression.

Gene→Variant (gene-first): 4843:C118S 4843:G353>C 4846:S1177D

Genes: 4843 4846

Variants: C118S G353>C S1177D

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the C118S mutation specifically blocks redox-dependent reactions that lead to Ras activation, indicating an alteration in molecular function. Oncogenic: The context of the study involves investigating the effect of the C118S mutation on Ras function during tumorigenesis, suggesting that this somatic variant contributes to tumor development or progression.

Gene→Variant (gene-first): 4843:C118 4843:C118S 4843:G353 transversion to C 4843:G353>C

Genes: 4843

Variants: C118 C118S G353 transversion to C G353>C