[Paper-level Aggregated] PMCID: PMC4654747

Evidence Type(s): Oncogenic, Prognostic, Functional

Justification: Oncogenic: The study indicates that mutations in histone H3, specifically K27M and K27I, drive distinct oncogenic programs in DIPG, with H3.3-K27M mutations leading to a proneural/oligodendroglial phenotype and a pro-metastatic gene expression signature. Prognostic: The findings demonstrate that patients with H3.1-K27M mutations have a better overall survival and clinical response to radiotherapy compared to those with H3.3-K27M mutations, indicating that the type of histone mutation is a significant prognostic factor. Functional: The study assesses the functional impact of histone mutations on gene expression profiles and tumor behavior, showing that specific mutations lead to alterations in trimethylation and gene expression that influence tumor characteristics and patient outcomes.

Gene→Variant (gene-first): TP53(7157):83A>T MYCN(4613):84G>T H3-3B(3021):K27I H3-3B(3021):K27M H3C14(126961):lysine-to-isoleucine TLX2(3196):G34R/V H3-3B(3021):lysine 27

Genes: TP53(7157) MYCN(4613) H3-3B(3021) H3C14(126961) TLX2(3196)

Variants: 83A>T 84G>T K27I K27M lysine-to-isoleucine G34R/V lysine 27

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 14

Evidence Type(s): Diagnostic, Prognostic, Oncogenic

Justification: Diagnostic: The passage discusses the association of H3.1-K27M tumors with clinical characteristics and outcomes, indicating its role in defining and classifying the disease. Prognostic: The variant K27M is correlated with overall survival outcomes, with H3.1 mutations showing a better prognosis compared to H3.3 mutations, independent of therapy. Oncogenic: The mention of H3.1-K27M tumors suggests that this somatic variant contributes to tumor development or progression, as it is associated with clinical characteristics and outcomes in cancer patients.

Gene→Variant (gene-first): 3021:K27M

Genes: 3021

Variants: K27M

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 13

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The K27M mutation is associated with disease behavior, indicating a correlation with disease outcome, specifically suggesting a less aggressive behavior in DIPG. Diagnostic: The mention of the K27M mutation being associated with DIPG suggests its role in defining or classifying this specific disease subtype.

Gene→Variant (gene-first): 3021:K27M

Genes: 3021

Variants: K27M

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 11

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the strong enrichment of the K27M variant in specific tumor subtypes, indicating its association with the proneural-glioblastoma multiforme (GBM) and oligodendrocytic or neural signatures, which helps classify the disease. Oncogenic: The K27M variant is implicated in tumor development, as evidenced by its association with oligodendroglial differentiation and the observation of metastatic relapse in patients with H3F3A mutations, suggesting a role in tumor progression.

Gene→Variant (gene-first): 3021:K27M

Genes: 3021

Variants: K27M

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage indicates that K27M mutations in H3.3 and H3.1 contribute to distinct oncogenic programs, suggesting their role in tumor development or progression.

Gene→Variant (gene-first): 3021:K27M

Genes: 3021

Variants: K27M

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 9

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the exclusive presence of the K27M variant in specific tumor subgroups (H3.1-K27M and H3.3-K27M), indicating its role in classifying these tumors. Oncogenic: The K27M variant is associated with specific tumor subgroups and is implicated in tumor development, as indicated by its exclusive presence in H3.1 and H3.3 tumors.

Gene→Variant (gene-first): 3021:K27M

Genes: 3021

Variants: K27M

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the identification of specific mutations (H3.3-K27M, H3-G34R/V, H3.1- and H3.2-K27M, H3.3 K27I) in different tumor locations, indicating their association with specific tumor types, which supports their use in defining or classifying disease subtypes. Oncogenic: The mention of mutations being identified in specific tumor types suggests that these variants contribute to tumor development or progression, indicating their oncogenic potential.

Gene→Variant (gene-first): 3196:G34R/V 3021:K27I 3021:K27M

Genes: 3196 3021

Variants: G34R/V K27I K27M

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 4

Evidence Type(s): Diagnostic, Functional

Justification: Diagnostic: The passage discusses the detection of H3-K27M mutations and their association with immunohistochemistry (IHC) staining, indicating the use of these variants to classify or define a subtype of disease. Functional: The passage mentions the loss of H3K27me3 immunoexpression associated with the K27I variant, indicating an alteration in molecular function related to protein activity or modification.

Gene→Variant (gene-first): 7157:83A>T 4613:84G>T 3021:K27I 3021:K27M 126961:lysine-to-isoleucine

Genes: 7157 4613 3021 126961

Variants: 83A>T 84G>T K27I K27M lysine-to-isoleucine

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 3

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the correlation of the H3-K27M mutation with the classification of DIPG samples, indicating its role in defining or confirming the disease subtype. Oncogenic: The mention of the H3-K27M mutation in the context of tumor samples suggests that it contributes to tumor development or progression, characteristic of oncogenic variants.

Gene→Variant (gene-first): 3021:K27M 3021:lysine 27

Genes: 3021

Variants: K27M lysine 27

[Paragraph-level] PMCID: PMC4654747 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The passage discusses how mutations in histone H3, specifically K27M and K27I, contribute to tumor development and progression in diffuse intrinsic pontine glioma (DIPG), indicating their role as somatic variants driving distinct oncogenic programs. Predictive: The K27M mutation is associated with a lack of clinical response to radiotherapy and earlier relapse, suggesting that this variant correlates with treatment resistance and impacts patient outcomes.

Gene→Variant (gene-first): 3021:K27I 3021:K27M 126961:lysine-to-isoleucine

Genes: 3021 126961

Variants: K27I K27M lysine-to-isoleucine