[Paper-level Aggregated] PMCID: PMC5629366

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

Justification: Oncogenic: The text discusses the development of a novel IDH1 inhibitor targeting various IDH1R132 mutations, indicating that these mutations are associated with oncogenic activity in AML cells. Functional: The evidence shows that BAY1436032 inhibits the enzymatic function of mutant IDH1 proteins and alters histone and DNA methylation patterns in AML cells, demonstrating a functional impact on cellular processes. Predictive: The sensitivity of patient-derived AML cells with IDH1R132 mutations to BAY1436032 suggests that these mutations can predict the efficacy of the treatment. Prognostic: The presence of IDH1R132 mutations and their response to BAY1436032 may provide prognostic information regarding the potential outcomes in AML patients treated with this inhibitor.

Gene→Variant (gene-first): IDH1(3417):R132C IDH1(3417):R132G IDH1(3417):R132H IDH1(3417):R132L IDH1(3417):R132S IDH2(3418):R140Q FLT3(2322):p.D835del NRAS(4893):p.Q61R

Genes: IDH1(3417) IDH2(3418) FLT3(2322) NRAS(4893)

Variants: R132C R132G R132H R132L R132S R140Q p.D835del p.Q61R

[Paragraph-level] PMCID: PMC5629366 Section: RESULTS PassageIndex: 18

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the treatment of AML cells with BAY1436032 and its effects on DNA methylation, indicating a correlation between the IDH1R132H mutation and the response to this specific therapy. Functional: The passage describes how the IDH1R132H mutation affects DNA methylation patterns and gene expression, demonstrating an alteration in molecular function due to the variant.

Gene→Variant (gene-first): 3417:R132H

Genes: 3417

Variants: R132H

[Paragraph-level] PMCID: PMC5629366 Section: RESULTS PassageIndex: 17

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the response of IDH1 mutant AML cells, including those with the R132H mutation, to the treatment with BAY1436032, indicating a correlation with therapy response. Functional: The passage describes how the R132H variant alters histone methylation levels, demonstrating a change in molecular function related to histone demethylation.

Gene→Variant (gene-first): 3417:R132H

Genes: 3417

Variants: R132H

[Paragraph-level] PMCID: PMC5629366 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the treatment of PDX models with BAY1436032, indicating a correlation between the variant mutations and the response to this specific therapy. Oncogenic: The passage describes the presence of somatic mutations (p.D835del and p.Q61R) in AML cells that contribute to tumor development, as evidenced by their propagation in PDX models.

Gene→Variant (gene-first): 2322:p.D835del 4893:p.Q61R

Genes: 2322 4893

Variants: p.D835del p.Q61R

[Paragraph-level] PMCID: PMC5629366 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the sensitivity of various IDH1R132 mutant proteins to the IDH1 inhibitor BAY1436032, indicating a correlation between the presence of these variants and the response to the therapy. Oncogenic: The variants mentioned (R132C, R132G, R132H, R132L, R132S) are associated with mutant IDH1 proteins that contribute to tumor development, as evidenced by their expression in patient-derived AML cells and their role in producing R-2HG.

Gene→Variant (gene-first): 3417:R132C 3417:R132G 3417:R132H 3417:R132L 3417:R132S 3418:R140Q

Genes: 3417 3418

Variants: R132C R132G R132H R132L R132S R140Q