[Paper-level Aggregated] PMCID: PMC1240052

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The text describes how mutations such as L858R and G719S in the EGFR gene can transform NIH-3T3 cells, leading to anchorage independence and tumor formation in immunocompromised mice, indicating their oncogenic potential. Predictive: The presence of activating EGFR mutations, including L858R and G719S, is associated with clinical responses to EGFR inhibitors like gefitinib and erlotinib in lung adenocarcinoma patients, suggesting these mutations can predict treatment outcomes. Functional: The study demonstrates that mutant EGFRs, including L858R and G719S, exhibit constitutive activation of downstream signaling pathways, such as STAT3 and Akt, indicating functional alterations in signaling due to these mutations.

Gene→Variant (gene-first): EGFR(1956):A750P EGFR(1956):D770_N771insNPG EGFR(1956):E749del EGFR(1956):G719S EGFR(1956):L858R EGFR(1956):L747_E749del A750P HRAS(3265):V12 EGFR(1956):D837A AKT1(207):serine/threonine

Genes: EGFR(1956) HRAS(3265) AKT1(207)

Variants: A750P D770_N771insNPG E749del G719S L858R L747_E749del A750P V12 D837A serine/threonine

[Paragraph-level] PMCID: PMC1240052 Section: RESULTS PassageIndex: 19

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the effectiveness of the irreversible EGFR inhibitor CL-387,785 in inhibiting colony formation and autophosphorylation in cells expressing the L858R variant, indicating a correlation with treatment response. Oncogenic: The L858R variant is described in the context of its role in transformation assays, suggesting that it contributes to tumor development or progression.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC1240052 Section: RESULTS PassageIndex: 16

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the correlation between the presence of activating EGFR mutations, including G719S, L747_E749del A750P, and L858R, and clinical responses to gefitinib or erlotinib, indicating their sensitivity to these therapies. Oncogenic: The passage describes the ability of the mentioned EGFR mutations to promote anchorage-independent growth in cell lines, which is indicative of their role in tumor development or progression.

Gene→Variant (gene-first): 1956:G719S 1956:L747_E749del A750P 1956:L858R

Genes: 1956

Variants: G719S L747_E749del A750P L858R

[Paragraph-level] PMCID: PMC1240052 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the mutant EGFR leads to the constitutive activation of the serine/threonine kinase Akt, indicating an alteration in molecular function related to cell survival signaling pathways.

Gene→Variant (gene-first): 207:serine/threonine

Genes: 207

Variants: serine/threonine

[Paragraph-level] PMCID: PMC1240052 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage describes how the L858R mutant EGFR alters molecular function by activating STAT signaling pathways and increasing STAT3-dependent gene expression, as demonstrated through immunoblotting and reporter assays. Oncogenic: The L858R variant is associated with transformed NIH-3T3 cells, indicating its contribution to tumor development or progression.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC1240052 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the L858R variant of EGFR alters the molecular function of Shc binding and phosphorylation, indicating a change in biochemical activity associated with the mutant protein. Oncogenic: The L858R variant is described as contributing to constitutive activation of EGFR, which is associated with tumor development or progression, as evidenced by the downstream signaling alterations observed in the study.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC1240052 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the L858R variant alters the molecular function of EGFR, specifically its autophosphorylation activity in response to EGF stimulation, indicating a change in biochemical function. Oncogenic: The L858R variant is associated with tumor development, as it is mentioned in the context of a lung adenocarcinoma cell line, suggesting its role in cancer progression.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC1240052 Section: RESULTS PassageIndex: 6

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes how the mutant forms of EGFR (L858R, G719S, L747_E749del A750P, and D770_N771insNPG) contribute to enhanced anchorage-independent growth in hTBE cells, indicating their role in tumor development or progression. Functional: The passage discusses the expression levels of the deletion and insertion mutants (L747_E749del A750P and D770_N771insNPG) and their ability to form colonies in soft agar, suggesting alterations in molecular function related to tumorigenesis.

Gene→Variant (gene-first): 1956:D770_N771insNPG 1956:G719S 1956:L747_E749del A750P 1956:L858R 3265:V12

Genes: 1956 3265

Variants: D770_N771insNPG G719S L747_E749del A750P L858R V12

[Paragraph-level] PMCID: PMC1240052 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses how the EGFR variants A750P, D770_N771insNPG, L747_E749del, L858R, and G719S contribute to tumor development, as evidenced by their ability to form colonies in soft agar and exhibit loss of contact inhibition in NIH-3T3 cells.

Gene→Variant (gene-first): 1956:A750P 1956:D770_N771insNPG 1956:E749del 1956:G719S 1956:L858R

Genes: 1956

Variants: A750P D770_N771insNPG E749del G719S L858R

[Paragraph-level] PMCID: PMC1240052 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes how the L858R and G719S EGFR variants contribute to tumor development, as evidenced by their ability to transform NIH-3T3 cells and form tumors in immunocompromised mice. Functional: The passage indicates that the expression of the EGFR point mutants (L858R and G719S) in NIH-3T3 cells caused loss of contact inhibition, suggesting that these variants alter the molecular function of the EGFR protein.

Gene→Variant (gene-first): 1956:D837A 1956:G719S 1956:L858R

Genes: 1956

Variants: D837A G719S L858R

[Paragraph-level] PMCID: PMC1240052 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the ability of the G719S and L858R mutations to transform NIH-3T3 cells, indicating that these somatic variants contribute to tumor development. Functional: The passage describes how the mutations G719S and L858R alter the ability of EGFR to induce colony formation in soft agar, demonstrating a change in molecular function related to tumorigenesis.

Gene→Variant (gene-first): 1956:D837A 1956:G719S 1956:L858R

Genes: 1956

Variants: D837A G719S L858R