As we have been unable to obtain suitable crystals of the insASV or insSVD variants, we determined cocrystal structures of BAY-33, TAK-788, TAS6417, and poziotinib with WT EGFR to better understand their binding modes an
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 14
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 1956:T790M 1956:V948R
Genes: 1956
Variants: T790M V948R
To better understand the degree of correlation in drug sensitivity across WT and various EGFR mutants, we plotted pairwise comparisons of IC50 values (Fig. 2). This analysis revealed little if any correlation in inhibito
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the correlation between the L858R variant and drug sensitivity, indicating that the L858R mutation has a drug-sensitizing effect, which aligns with predictive evidence regarding therapy response. Oncogenic: The L858R variant is implicated in greater potency against EGFR compared to WT EGFR, suggesting its role in tumor development or progression, which is characteristic of oncogenic evidence.
Gene→Variant (gene-first): 1956:L858R
Genes: 1956
Variants: L858R
We measured the biochemical potencies of a diverse panel of EGFR inhibitors against insASV, insSVD, and insNPG exon 20 insertion mutants and for comparison against WT EGFR and the L858R and L858R/T790M point mutants. Inh
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the measurement of biochemical potencies of EGFR inhibitors against specific mutants, including L858R and L858R/T790M, indicating a correlation with response to therapy. Functional: The passage describes the use of recombinant EGFR kinase proteins in assays to evaluate the biochemical activity of inhibitors, which implies that the variants may alter molecular function.
Gene→Variant (gene-first): 1956:L858R 1956:T790M
Genes: 1956
Variants: L858R T790M
The enhanced inhibitor sensitivity of EGFR L858R and exon 19 deletions stems, at least in part, from their decreased affinity for ATP compared to the WT EGFR. While the Km, ATP values of insASV and insSVD are higher as c
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 5
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the enhanced inhibitor sensitivity of the L858R variant in relation to its decreased affinity for ATP, indicating a correlation with sensitivity to EGFR TKIs, which aligns with predictive evidence. Oncogenic: The passage implies that the L858R variant contributes to oncogenicity, as it discusses the variant's biochemical properties and their relation to tumor development and progression.
Gene→Variant (gene-first): 1956:L858R
Genes: 1956
Variants: L858R
We used a coupled enzyme assay to determine enzyme kinetic parameters for these exon 20 insertions, as well as for WT, L858R, and L858R/T790M EGFR for comparison. This well-established continuous assay employs pyruvate k
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 4
Evidence Type(s): Functional
Justification: Functional: The passage discusses enzyme kinetic parameters and catalytic efficiencies of the L858R variant and other variants, indicating that these variants alter molecular function as demonstrated by the enzyme assays.
Gene→Variant (gene-first): 7294:Glu4 1956:L858R 1956:T790M
Genes: 7294 1956
Variants: Glu4 L858R T790M
After transfection, the cells were allowed to grow for 24 h and then lysed. The level of EGFR-mCherry and wild-type and S310F HER2-eGFP in the cell lysate was determined by measuring the fluorescence intensity. After a c
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 11
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the S310F variant of HER2 interacts with EGFR and compares its efficiency to wild-type HER2, indicating an alteration in molecular function.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
Single molecule interaction analysis was performed to determine whether the S310F HER mutant formed a heterodimer with the EGFR. We constructed a bicistronic mammalian expression vector encoding EGFR-mCherry and S310F HE
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 10
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the interaction of the S310F HER2 mutant with EGFR and its altered reactivity to specific antibodies, indicating a change in molecular function. Oncogenic: The S310F HER2 variant is implicated in altered interactions that may contribute to tumor development or progression, as suggested by the context of the study involving cancer-related proteins.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
3.4. Single-Molecular Interaction Analysis Demonstrated That the S310F HER2 Mutant Formed Heterodimers with the EGFR
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 9
Evidence Type(s): Functional
Justification: Functional: The passage indicates that the S310F variant alters the molecular interaction by forming heterodimers with EGFR, suggesting a change in biochemical function.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
We tested the effects of anti-HER2 agents on 5637 cell proliferation and the level of HER2 phosphorylation at Y1221 and Y1222 residues. The cells were incubated with pertuzumab, trastuzumab and lapatinib for 96 h, lysed
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 8
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the effects of anti-HER2 agents on cell proliferation and HER2 phosphorylation in relation to the S310F HER2 mutant, indicating a correlation with response to specific therapies. Oncogenic: The S310F variant is implicated in the phosphorylation process and cell proliferation in cancer cells, suggesting its role in tumor development or progression.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
3.3. EGFR Activates S310F HER2 Mutant in 5637 Cell
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage indicates that the S310F variant in HER2 is associated with activation in a cell line, suggesting its role in tumor development or progression.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
To confirm the expression of the S310F HER2 mutant in 5637 cells, we used immunoprecipitation experiments. We hypothesized that if the cells expressed the S310F HER2 mutant, it would not be immunoprecipitated by pertuzum
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 6
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the expression of the S310F HER2 mutant and its interaction with pertuzumab, indicating that the variant alters the molecular function of HER2 in terms of immunoprecipitation. Oncogenic: The S310F variant is described in the context of its expression in cancer cell lines, suggesting that it may contribute to tumor development or progression.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
We searched literatures to identify a human cell line expressing the S310F mutant and found that bladder cancer cell line 5637 expressed the mutant. To test the allelic expression of the S310F HER2 mutant in the 5637 cel
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 5
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the expression and detection of the S310F HER2 mutant in a bladder cancer cell line, indicating that the variant alters the molecular function of the HER2 protein as it is being analyzed for its presence on the cell surface. Oncogenic: The S310F variant is discussed in the context of a bladder cancer cell line, suggesting that it may contribute to tumor development or progression, which aligns with the definition of an oncogenic variant.
Gene→Variant (gene-first): 2064:S310 2064:S310F
Genes: 2064
Variants: S310 S310F
3.2. A Bladder Cancer Cell Line, 5637, Expresses Both Wild-Type HER2 and S310F Mutant
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 4
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
A construct encoding the S310F HER2 extracellular domain fused to a human Fc domain of immunoglobulin heavy chain was prepared and cloned into a mammalian expression vector. For comparison, the expression vectors encodin
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the binding interactions of various HER2 mutants with the antibodies pertuzumab and trastuzumab, indicating their response to these therapies. Functional: The passage describes the preparation and purification of recombinant fusion proteins and their binding characteristics, which suggests alterations in molecular function related to the HER2 mutants.
Gene→Variant (gene-first): 2064:G309 2064:G309A 2064:G309E 2064:S309A 2064:S310 2064:S310F 2064:S310Y
Genes: 2064
Variants: G309 G309A G309E S309A S310 S310F S310Y
3.1. The Recombinant S310F Mutant Is Not Reactive to Pertuzumab but Binds to Trastuzumab
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 2
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage indicates that the S310F mutant is not reactive to Pertuzumab, suggesting a correlation with resistance to this specific therapy. Functional: The passage discusses the binding characteristics of the S310F mutant, indicating an alteration in molecular function related to its interaction with Trastuzumab.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
KIT kinase V559D mutation is the most prevalent primary gain-of-function mutation in Gastrointestinal Stromal Tumors (GISTs). Here we reported a highly selective KIT V559D inhibitor CHMFL-KIT-031, which displayed about 1
[Paragraph-level] PMCID: PMC5762309 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the selective inhibitor CHMFL-KIT-031 and its efficacy against the KIT V559D mutation, indicating a correlation with response to therapy. Oncogenic: The KIT V559D mutation is described as a primary gain-of-function mutation in GISTs, suggesting it contributes to tumor development or progression.
Gene→Variant (gene-first): 3815:D816V 3815:L576P 3815:N822K 3815:T670I 3815:V559D 3815:V654A
Genes: 3815
Variants: D816V L576P N822K T670I V559D V654A
Recent advances in molecular profiling technologies allow genetic driver events in individual tumors to be identified. The hypothesis behind this ongoing molecular profiling effort is that improvement in patients' clinic
[Paragraph-level] PMCID: PMC5002925 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the treatment of a patient with advanced colorectal cancer using trastuzumab based on the presence of the ERBB2 p.L755S mutation, indicating a correlation with therapy response. Oncogenic: The mention of the ERBB2 p.L755S mutation as a genetic driver event in the context of advanced colorectal cancer suggests its role in tumor development or progression.
Gene→Variant (gene-first): 2064:p.L755S 673:p.N581S 324:p.Q1429fs
Genes: 2064 673 324
Variants: p.L755S p.N581S p.Q1429fs
In June 2013, profiling of sample 2 (tumor cell content 80%) using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (detailed in the Methods section) showed a heterozygous somatic
[Paragraph-level] PMCID: PMC5002925 Section: RESULTS PassageIndex: 6
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses heterozygous somatic mutations, including ERBB2 p.L755S, APC p.Q1429fs, and BRAF p.N518S, which are associated with tumor development and progression, indicating their oncogenic potential. Functional: The passage mentions that the biological effect of the detected mutations was predicted using algorithms, suggesting an alteration in molecular or biochemical function related to these variants.
Gene→Variant (gene-first): 2064:p.L755S 673:p.N518S 673:p.N581S 324:p.Q1429fs
Genes: 2064 673 324
Variants: p.L755S p.N518S p.N581S p.Q1429fs
A 35-yr-old male, who was treated with a laparoscopic low anterior resection in June 2008 for a stage I (pT2N0M0) KRAS and NRAS wild-type, moderately differentiated, microsatellite stable rectal adenocarcinoma, developed
[Paragraph-level] PMCID: PMC5002925 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the treatment response to therapies such as trastuzumab and FOLFIRI, which are influenced by the presence of specific somatic mutations, indicating a correlation between the variants and treatment response. Oncogenic: The passage identifies somatic mutations in the tumors that are associated with tumor development and progression, particularly noting the likely activating mutation in the ERBB2 p.L755S variant.
Gene→Variant (gene-first): 673:c.1742A>G 2064:c.2264T>C 324:c.4285delC 673:p.Asn581Ser 324:p.Gln1429fs 2064:p.L755S 2064:p.Leu755Ser 673:p.N581S 324:p.Q1429fs
Genes: 673 2064 324
Variants: c.1742A>G c.2264T>C c.4285delC p.Asn581Ser p.Gln1429fs p.L755S p.Leu755Ser p.N581S p.Q1429fs
In keeping with the identification of KRAS and/or NRAS mutations as the dominant genomic change associated with treatment resistance, serial ctDNA analysis was able to reveal the emergence of these mutations prior to dis
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 24
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the emergence of KRAS mutations associated with treatment resistance, indicating a correlation with response to therapy, specifically in the context of chemotherapy and targeted treatments. Oncogenic: The passage describes the identification of KRAS mutations that contribute to tumor progression, particularly noting the emergence of these mutations prior to disease progression, which is indicative of their role in cancer development.
Gene→Variant (gene-first): 3791:A163G 3845:G12D 3845:G12N 3845:G13D 3845:Q61H 4893:Q61L 79811:R106H 673:V600E
Genes: 3791 3845 4893 79811 673
Variants: A163G G12D G12N G13D Q61H Q61L R106H V600E
Plasma DNA collected at the time of disease progression was analyzed through targeted sequencing to identify evidence of genomic evolution following treatment and potential mechanisms of acquired resistance to therapy. I
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 23
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses the retention of the BRAF V600E mutation in patients with mCRC, indicating its role in tumor development or progression, particularly in the context of disease progression and treatment response.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
The ratio of BRAF V600E mutation VAF on treatment at week 2 and week 4, relative to baseline was assessed as a predictor of PFS and OS. Most patients (19/21; 91%) had a week 2-baseline ratio (W2-BLR) of <1, with a median
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 20
Evidence Type(s): Prognostic, Predictive
Justification: Prognostic: The passage discusses how the BRAF V600E mutation VAF ratio correlates with progression-free survival (PFS) and overall survival (OS), indicating that it is associated with disease outcomes independent of therapy. Predictive: The assessment of the BRAF V600E mutation VAF ratio as a predictor of PFS and OS suggests that it may correlate with treatment response, indicating its predictive value in the context of therapy.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
We next explored whether early, dynamic changes in ctDNA levels were predictive of outcomes to combination vemurafenib and erlotinib therapy. A total of 25 paired baseline-week 2 (BL-W2) and 21 paired baseline-week 4 (BL
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 19
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how early changes in ctDNA levels, specifically related to the BRAF V600E variant, are predictive of clinical benefit and objective response to combination vemurafenib and erlotinib therapy. Oncogenic: The BRAF V600E variant is implicated in tumor dynamics and is associated with the response to treatment, indicating its role in tumor development or progression.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
In addition to ddPCR testing, baseline plasma DNA was analyzed using a targeted capture based next-generation sequencing assay (Avenio Expanded panel, Roche Diagnostics; Supplementary Table S1 for list of genes). At leas
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 16
Evidence Type(s): Predictive, Diagnostic, Oncogenic
Justification: Predictive: The passage indicates that the presence of genetic alterations, including the NRAS G13C mutation, correlates with clinical benefit from treatment, suggesting a predictive relationship regarding therapy response. Diagnostic: The mention of the NRAS G13C mutation being detected in a patient implies its role in identifying or classifying the disease, which aligns with diagnostic evidence. Oncogenic: The NRAS G13C mutation is discussed in the context of being a mutation found in a patient, which suggests its potential role in tumor development or progression.
Gene→Variant (gene-first): 4893:G13C
Genes: 4893
Variants: G13C
Twenty-five patients had serial plasma available for ctDNA analyses (Fig. 3A). Baseline pretreatment plasma DNA analyzed by droplet digital PCR (ddPCR) was positive for BRAF V600E mutant ctDNA in 21 of 25 patients (84%).
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 15
Evidence Type(s): Diagnostic, Prognostic, Oncogenic
Justification: Diagnostic: The passage indicates that BRAF V600E mutant ctDNA is detected in a significant proportion of patients, suggesting its use in defining or confirming the presence of a specific disease. Prognostic: The passage states that higher levels of ctDNA at baseline are associated with inferior progression-free survival (PFS) and overall survival (OS), indicating a correlation with disease outcome independent of therapy. Oncogenic: The presence of the BRAF V600E variant in ctDNA suggests its role in tumor development or progression, as it is a known somatic mutation associated with cancer.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
A total of 40 patients were enrolled across the dose escalation and dose expansion phases (mCRC n = 33 and non-CRC cohort n = 7) between July 2014 and August 2017 (Fig. 1A). The non-colorectal cancer cohort included 7 pa
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage mentions that the non-colorectal cancer cohort included patients who were BRAF V600E mutation positive, indicating that this variant is used to classify or define a specific group of patients with selected cancers. Oncogenic: The BRAF V600E mutation is associated with tumor development in various cancers, as indicated by its presence in patients with selected cancers, suggesting its role in oncogenesis.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for a tenth of all EGFR mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion mutants that
[Paragraph-level] PMCID: PMC8700411 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Diagnostic, Oncogenic
Justification: Predictive: The passage discusses the sensitivity of specific EGFR variants (D770 and G770) to various EGFR-TKIs, indicating a correlation with response to therapy. Diagnostic: The mention of EGFR exon 20 insertion mutations and their frequency in lung cancer suggests that these variants are used to classify and define a specific subtype of the disease. Oncogenic: The variants D770 and G770 are described as contributing to tumor development, as they are part of the EGFR mutations associated with lung cancer.
Gene→Variant (gene-first): 1956:D770 1956:G770 1956:Y764insFQEA
Genes: 1956
Variants: D770 G770 Y764insFQEA
Although these cases are limited in number and by reporting biases, they provide supporting evidence that EGFR-D770>GY and other exon 20 insertion mutations with G770 equivalence are sensitive to the clinically available
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive
Justification: Predictive: The passage indicates that the variant G770 and other exon 20 insertion mutations are sensitive to specific EGFR TKIs, suggesting a correlation with treatment response.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
The majority:but not all:of cases that received poziotinib or mobocertinib in this compiled cohort of advanced lung cancers harboring EGFR exon 20 insertion mutations with G770 equivalence had radiographic responses (Tab
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the correlation between the G770 variant and radiographic responses to therapies (poziotinib and mobocertinib) in advanced lung cancers, indicating its predictive nature regarding treatment response. Diagnostic: The mention of "EGFR exon 20 insertion mutations with G770 equivalence" suggests that the G770 variant is used to classify or define a specific subtype of lung cancer, supporting its role as a diagnostic marker.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
We identified seven reports from the literature and added one case from our institutional cohort that detailed partial clinical-radiographic parameters in patients with metastatic lung cancers harboring EGFR exon 20 inse
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of patients with metastatic lung cancers harboring EGFR exon 20 insertion mutations, including G770, to various EGFR TKIs, indicating a correlation with treatment response. Oncogenic: The mention of tumors harboring EGFR exon 20 insertion mutations, including G770, suggests that this somatic variant contributes to tumor development or progression in the context of metastatic lung cancers.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
3.3. Clinical Outcomes of Reported Patients with Advanced Lung Cancers Harboring EGFR Exon 20 Insertion Mutations Encompassing G770 Equivalence
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 9
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses patients with advanced lung cancers harboring EGFR Exon 20 insertion mutations, indicating that the variant is used to classify or define a specific disease subtype. Oncogenic: The mention of advanced lung cancers suggests that the G770 variant contributes to tumor development or progression, aligning with the definition of an oncogenic variant.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
Our aforementioned preclinical results confirmed the structural modeling of EGFR-D770>GY (Figure 1A) and led us to speculate that patients with advanced lung cancers harboring EGFR exon 20 insertion mutations with a G770
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 8
Evidence Type(s): Predictive
Justification: Predictive: The passage discusses the potential response of patients with advanced lung cancers harboring the G770 variant to specific therapies, indicating a correlation with treatment response.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
The exquisite sensitivity to 2nd generation EGFR TKIs was confirmed at the biochemical level. In Western blot experiments, the phosphorylated form of EGFR was readily inhibited by 10 nM and higher doses of dacomitinib in
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the sensitivity of the V769dupASV variant to 2nd generation EGFR TKIs, indicating a correlation with response to therapy. Functional: The variant V769dupASV is shown to alter the biochemical function of EGFR, as evidenced by the differing levels of inhibition of phosphorylated EGFR in response to dacomitinib.
Gene→Variant (gene-first): 1956:V769dupASV
Genes: 1956
Variants: V769dupASV
To highlight the differences in proliferation assays between Ba/F3 cells driven by the EGFR-D770>GY mutant and the more typical EGFR-A767_V769dupASV mutant, we show the dose-response curve for increasing concentrations o
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 6
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of cells with the A767_V769dupASV mutant to specific therapies (afatinib and dacomitinib), indicating a correlation between the variant and treatment sensitivity. Oncogenic: The variant A767_V769dupASV is mentioned in the context of proliferation assays, suggesting that it contributes to tumor development or progression in the tested cell lines.
Gene→Variant (gene-first): 1956:V769dupASV
Genes: 1956
Variants: V769dupASV
Our group generated a Ba/F3 cell line driven by the EGFR-D770>GY mutant in order to compare its properties with our previously described isogenic Ba/F3 preclinical models of exon 20 insertion mutants (Figure 2). To evalu
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 5
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the sensitivity and resistance of various EGFR mutations, including D770_N771insSVD, V769dupASV, and Y764insFQEA, to different EGFR TKIs, indicating a correlation with response to therapy. Oncogenic: The variants mentioned are associated with the development of cancer, as they are described in the context of a Ba/F3 cell line model driven by specific EGFR mutations, which contribute to tumor behavior.
Gene→Variant (gene-first): 1956:D770_N771insSVD 1956:V769dupASV 1956:Y764insFQEA
Genes: 1956
Variants: D770_N771insSVD V769dupASV Y764insFQEA
3.2. Preclinical Characterization of an EGFR Exon 20 Insertion Mutant with a G770 Equivalence
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 4
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
We queried three separate cohorts of EGFR exon 20 insertion mutations. Out of the 429 cases reported, 17 (3.96%) had the EGFR mutation leading to G770 equivalent change in the context of an insertion (Figure 1B). The typ
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the prevalence of the G770 variant in a cohort of cases with EGFR exon 20 insertion mutations, indicating its association with a specific mutation type and providing context for its classification. Oncogenic: The mention of the G770 variant in the context of EGFR mutations suggests its role in tumor development or progression, as it is part of a known oncogenic pathway associated with cancer.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
3.1. Frequency of EGFR Exon 20 Insertions with a G770 Equivalence
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 2
Evidence Type(s): Diagnostic
Justification: Diagnostic: The mention of "frequency" in relation to "EGFR Exon 20 Insertions with a G770 Equivalence" suggests that the variant is being used to classify or define a specific disease or subtype.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
In addition, the ADx-ARMS identified 2 samples with both 19 del and L858R mutation, 4 with both 19 del and T790M mutation, and 1 with both L858R and L861Q or S768I (The two spots were designed in one tube, we could not d
[Paragraph-level] PMCID: PMC3287118 Section: RESULTS PassageIndex: 7
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 1956:L858R 1956:L861Q 1956:S768I 1956:T790M
Genes: 1956
Variants: L858R L861Q S768I T790M
These updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents
[Paragraph-level] PMCID: PMC9338780 Section: ABSTRACT PassageIndex: 8
Evidence Type(s): Predictive, Prognostic
Justification: Predictive: The passage discusses the clinical benefit of dabrafenib plus trametinib in BRAF V600E-mutant ATC, indicating a correlation with improved treatment response. Prognostic: The mention of improved long-term survival in patients with BRAF V600E-mutant ATC suggests a correlation with disease outcome independent of therapy.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
ROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC
[Paragraph-level] PMCID: PMC9338780 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the evaluation of dabrafenib plus trametinib in patients with BRAF V600E-mutant cancers, indicating a correlation with treatment response. Oncogenic: The mention of BRAF V600E in the context of a study for rare cancers suggests that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patient
[Paragraph-level] PMCID: PMC9338780 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the approval of combined therapy with dabrafenib plus trametinib for treatment of BRAF V600E-mutant anaplastic thyroid cancer, indicating a correlation with treatment response. Diagnostic: The mention of BRAF V600E as a specific mutation in anaplastic thyroid cancer suggests its role in defining or classifying the disease subtype.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
The present results suggested that acquired VOPP1-EGFR fusion gene with T790M potentially serve an additional resistance mechanism to first-generation EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC. And the presen
[Paragraph-level] PMCID: PMC8727519 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses T790M as a resistance mechanism to first-generation EGFR tyrosine kinase inhibitors, indicating its correlation with treatment response. Oncogenic: The mention of T790M in the context of an acquired resistance mechanism suggests that it contributes to tumor progression in EGFR-mutated NSCLC.
Gene→Variant (gene-first): 1956:T790M
Genes: 1956
Variants: T790M
In this case report, we describe a 69-year-old female who received right lobectomy and was diagnosed with pathological stage IIIA lung adenocarcinoma harboring EGFR L858R. Twenty months later he had recurrent disease in
[Paragraph-level] PMCID: PMC8727519 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the T790M variant as a potential resistance mechanism to icotinib treatment, indicating its correlation with treatment response. Oncogenic: The L858R variant is described as being present in a patient with lung adenocarcinoma, suggesting its role in tumor development or progression.
Gene→Variant (gene-first): 1956:L858R 1956:T790M
Genes: 1956
Variants: L858R T790M
Taletrectinib continues to show high and durable overall responses, prolonged PFS, robust activity against intracranial lesions and acquired resistance mutations including G2032R, and a favorable safety profile with a lo
[Paragraph-level] PMCID: PMC11272140 Section: ABSTRACT PassageIndex: 8
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the variant G2032R in the context of acquired resistance mutations and mentions the overall responses and prolonged progression-free survival (PFS) associated with taletrectinib, indicating a correlation with treatment response. Oncogenic: The mention of G2032R as an acquired resistance mutation suggests that it contributes to tumor development or progression, particularly in the context of therapy resistance.
Gene→Variant (gene-first): 6098:G2032R
Genes: 6098
Variants: G2032R
As of November 2023, 173 patients were enrolled (median age, 55 years; 58% female; 73% never smoked; TKI naive: n = 106; crizotinib pretreated: n = 67). In TKI-naive patients, cORR and intracranial cORR were 91% and 88%,
[Paragraph-level] PMCID: PMC11272140 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Predictive
Justification: Predictive: The passage indicates that 67% of patients with G2032R mutations responded to treatment, suggesting a correlation between the variant and treatment response.
Gene→Variant (gene-first): 6098:G2032R
Genes: 6098
Variants: G2032R
Taletrectinib, a highly potent, CNS-active, ROS1 tyrosine kinase inhibitor (TKI), has demonstrated high and durable response rates, high intracranial objective response rate (ORR), prolonged progression-free survival (PF
[Paragraph-level] PMCID: PMC11272140 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the activity of taletrectinib against the G2032R variant, highlighting its correlation with high response rates and prolonged progression-free survival, indicating predictive evidence related to therapy response. Oncogenic: The mention of the G2032R variant in the context of ROS1+ non-small cell lung cancer suggests that it may contribute to tumor development or progression, aligning with oncogenic evidence.
Gene→Variant (gene-first): 6098:G2032R
Genes: 6098
Variants: G2032R
Some of the differences between the effects of tested inhibitors on activating FGFR variants (Figure 6) are consistent with observations from structural studies. Based on the crystal structure of FGFR1 KD V561M, the inte
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 33
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the expected efficacy of the JNJ42756493 inhibitor towards the FGFR3 V555M variant, indicating a correlation with response to therapy based on structural interactions. Functional: The passage mentions the interactions of inhibitors within the ATP-binding pocket of the FGFR1 KD V561M variant, suggesting that the variant alters molecular function related to drug binding and efficacy.
Gene→Variant (gene-first): 2261:V555M 2260:V561M
Genes: 2261 2260
Variants: V555M V561M
We further compared the effect of the two most potent FGFR-specific inhibitors AZD4547 and JNJ42756493 on hotspot mutations K650E and N540K in NIH3T3 cell lines. As previously reported and shown in Supplementary Figure S
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 32
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the effect of the K650E and N540K variants on the efficacy of FGFR-specific inhibitors, indicating a correlation with treatment response. Oncogenic: The variants K650E and N540K are discussed in the context of their impact on cellular transformation and response to inhibitors, suggesting their role in tumor development or progression.
Gene→Variant (gene-first): 2261:K650E 2261:N540K
Genes: 2261
Variants: K650E N540K
The impact of each mutation on drug binding is expressed as a fold-difference in Ki compared to the FGFR3 KD WT (Figure 6C). Highly activating R669G and, in particular, hotspot mutation K650E had moderate effects on the
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 31
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses how specific mutations, such as K650E, N540K, N540S, and V555M, affect the efficacy of various inhibitors, indicating a correlation with resistance or sensitivity to therapy. Functional: The passage describes how mutations like I538V and V555M alter the binding affinity and efficacy of inhibitors, which reflects changes in molecular function related to drug interactions.
Gene→Variant (gene-first): 2263:I538 2263:I538V 2261:K650E 2261:N540 2261:N540K 2261:N540S 2261:R669G 2261:V555M
Genes: 2263 2261
Variants: I538 I538V K650E N540 N540K N540S R669G V555M
We performed measurements of Ki for AZD4547, BGJ-398, TKI258, JNJ42756493 and AP24534 using purified FGFR3 KD WT and variants R669G, K650E, N540S, N540K, V555M and I538V (Figure 6, Supplementary Table S3). Ki values for
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 30
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the Ki values of various FGFR3 variants in response to specific inhibitors, indicating a correlation between the variants and their sensitivity to therapy. Functional: The mention of mutations affecting the ATP binding pocket and potential allosteric effects suggests that these variants alter the molecular function of the FGFR3 protein.
Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:N540K 2261:N540S 2261:R669G 2261:V555M
Genes: 2263 2261
Variants: I538V K650E N540K N540S R669G V555M
It is well established that some acquired mutations in protein kinases greatly reduce drug binding; the best-illustrated examples are gatekeeper mutations also described in FGFR3 (V555M). The question of how primary muta
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 29
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how mutations in protein kinases, such as V555M, can affect drug binding and implies a relationship between these mutations and drug efficacy, indicating a potential impact on treatment response. Oncogenic: The mention of V555M as an acquired mutation in FGFR3 suggests its role in tumor development or progression, particularly in the context of drug resistance.
Gene→Variant (gene-first): 2261:V555M
Genes: 2261
Variants: V555M
JNJ42756493 occupies the ATP-binding cleft of FGFR1 largely as expected on the basis of previous complexes between FGFR1 and other type-I inhibitors (e. g. BJG-398, AZD4547, PD173074 and TKI258) and where the activation
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 27
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the variants D641, L630, and V561 are involved in the binding interactions of the drug JNJ42756493 with FGFR1, indicating that these variants alter molecular interactions and contribute to the binding strength and specificity of the drug.
Gene→Variant (gene-first): 2260:D641 2260:L630 2260:V561
Genes: 2260
Variants: D641 L630 V561
Previous structural studies of FGFR2 KD highlighted a long-range allosteric communication linking the kinase hinge, the alphaC-helix and the A-loop. It was also illustrated that some A-loop mutations (such as FGFR3 K650E
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 24
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the K650E, R675G, and R669G mutations alter the allosteric communication and molecular interactions within the FGFR kinases, indicating a change in molecular function. Oncogenic: The mention of mutations that force an active conformation and alter the position of the alphaC-helix suggests that these variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2261:K650E 2261:R669G 2260:R675 2260:R675G
Genes: 2261 2260
Variants: K650E R669G R675 R675G
To gain further insight into the activation mechanism of the R669G mutation in FGFR3, we performed NMR studies in which we compared the backbone amide chemical shift perturbations (CSPs) associated with the R669G mutatio
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 23
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the R669G mutation alters molecular interactions and conformational changes in the FGFR3 protein, indicating an alteration in biochemical function.
Gene→Variant (gene-first): 2261:R669G
Genes: 2261
Variants: R669G
Comparison of this new FGFR1 R675G KD structure (Figure 4C, top) with inactive (apo) FGFR1 KD (PDB: 4UWY) and active, FGFR1-3P (pdb 3GQI) (Figure 4C, bottom) structures shows that FGFR1 R675G KD differs from the inactive
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 22
Evidence Type(s): Functional
Justification: Functional: The passage describes how the R675G variant alters the molecular interactions and conformation of the FGFR1 kinase domain, indicating a change in biochemical function.
Gene→Variant (gene-first): 2261:H650 2260:R675 2260:R675G 2263:Y653
Genes: 2261 2260 2263
Variants: H650 R675 R675G Y653
The residue corresponding to R669 in FGFR3 is conserved and also mutated in all other FGFRs in cancer as well as in FGFR2 in bone dysplasia (Supplementary Table S1). To assess the mechanism that underpins activation, we
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 21
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the R to G replacement and its impact on the activity of the FGFR1 KD variant, indicating that the variant alters molecular function. Oncogenic: The mention of the R669 and R675G variants being mutated in cancer suggests their contribution to tumor development or progression.
Gene→Variant (gene-first): 2260:R to G 2261:R669 2260:R675G
Genes: 2260 2261
Variants: R to G R669 R675G
Activation mechanism of FGFR3 R669G mutation
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 20
Evidence Type(s): Functional
Justification: Functional: The passage discusses the activation mechanism of the FGFR3 R669G mutation, indicating that it alters molecular or biochemical function.
Gene→Variant (gene-first): 2261:R669G
Genes: 2261
Variants: R669G
Comparison of our experimental data (Figure 2) with the assessments obtained using bioinformatics tools (Supplementary Table S1B and S1C) suggests that considering multiple methods together can provide insight into the i
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 19
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the variants E466K, D617G, and G637W are predicted to reduce protein production or completely inactivate the kinase, indicating an alteration in molecular function. Oncogenic: The mention of R669 being within an identified cluster of observed A-loop cancer mutations suggests that it contributes to tumor development or progression.
Gene→Variant (gene-first): 2261:D617G 2263:E466K 2260:G637W 2261:R669
Genes: 2261 2263 2260
Variants: D617G E466K G637W R669
Analysis of the FGFR3 R669G NIH3T3 cell line has shown that despite low expression levels, downstream signaling appeared to be enhanced as well as FGFR3 phosphorylation (Figure 4A).
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 18
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the R669G variant alters downstream signaling and FGFR3 phosphorylation, indicating a change in molecular function.
Gene→Variant (gene-first): 2261:R669G
Genes: 2261
Variants: R669G
It could be expected that some mutations that map to the KD do not affect kinase activity directly as measured under conditions in vitro. In particular, the hotspot G697C mutation which does not have an effect in such as
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 17
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the G697C mutation does not affect kinase activity directly as measured in vitro, indicating that it alters molecular function, specifically FGFR3 function, which can only be detected in a cellular setting. Oncogenic: The comparison of the FGFR3 G697C cell line with those expressing K650E and N540K shows that G697C does not lead to a transformed phenotype or anchorage-independent growth, suggesting it does not contribute to tumor development or progression like the other variants.
Gene→Variant (gene-first): 2261:G697C 2261:K650E 2261:N540K
Genes: 2261
Variants: G697C K650E N540K
From these direct measurements of kinase activity it seems that a considerable number of mutations reported so far result in kinase activation to some degree and that replacements that cause activation are not limited to
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 16
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the K650E variant alters kinase activity, indicating a change in molecular function related to activation. Oncogenic: The mention of the K650E variant in the context of kinase activation suggests its potential role in tumor development or progression.
Gene→Variant (gene-first): 2261:K650E
Genes: 2261
Variants: K650E
Two mutations, D617G and G637W, completely abolished kinase activity (Figure 2A and 2B, bottom panel). Both residues are strongly conserved among protein kinases and some of the replacements of these residues in various
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 15
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the mutations D617G and G637W abolish kinase activity, indicating that these variants alter the molecular function of the protein. Oncogenic: The passage mentions that the importance of these inactivating mutations for cancer development remains unclear, suggesting a potential role in tumor development or progression.
Gene→Variant (gene-first): 2261:D617 2261:D617G 2261:G to W 2260:G637 2260:G637W
Genes: 2261 2260
Variants: D617 D617G G to W G637 G637W
Twelve out of 26 analyzed mutations had very little or no effect on FGFR3 KD activity (Figure 2A and 2B, bottom panel). The number of observations in cancer for most of these mutations is low with the exception of G697C
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 14
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the effect of the G697C mutation on FGFR3 KD activity, indicating that it alters molecular function. Oncogenic: The mention of G697C as one of the hotspots suggests its potential role in tumor development or progression, which aligns with oncogenic behavior.
Gene→Variant (gene-first): 2261:G697C
Genes: 2261
Variants: G697C
Several other mutations, including V555M, D641G and D641N resulted in an increase of auto-phosphorylation up to 7-fold (Figure 2A) and a similar increase in substrate phosphorylation (Figure 2B, middle panel). The V555M
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive, Functional
Justification: Predictive: The V555M mutation is described as an acquired resistance mutation to an FGFR inhibitor, indicating a correlation with resistance to therapy. Functional: The passage discusses how the mutations, including V555M, D641G, and D641N, resulted in an increase in auto-phosphorylation and substrate phosphorylation, indicating an alteration in molecular function.
Gene→Variant (gene-first): 2260:D641G 2260:D641N 2261:V555 2261:V555M
Genes: 2260 2261
Variants: D641G D641N V555 V555M
Isolated FGFR KDs undergo auto-phosphorylation on several tyrosine residues and this property correlates well with the kinase activity towards natural and synthetic substrates. We used purified proteins of 26 FGFR3 KD va
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 12
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how different mutations in FGFR3 KD variants affect auto-phosphorylation and kinase activity, indicating that these variants alter molecular function. Oncogenic: The context of the passage suggests that the mutations contribute to tumor development or progression by enhancing kinase activity, which is a characteristic of oncogenic variants.
Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:K650N 2261:N540K 2261:N540S 2261:R669G 2261:R669Q
Genes: 2263 2261
Variants: I538V K650E K650N N540K N540S R669G R669Q
The number of cancer mutations in FGFR KDs that have been comprehensively assessed for their functional impact is limited, with the most emphasis being on replacements at positions corresponding to FGFR3 K650 and mutatio
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 11
Evidence Type(s): Functional
Justification: Functional: The passage discusses the functional impact of mutations at positions FGFR3 K650 and N540K, indicating that these variants are assessed for their effect on kinase activity.
Gene→Variant (gene-first): 2261:K650 2261:N540K
Genes: 2261
Variants: K650 N540K
A number of crystal structures of FGFR KD in non-phosphorylated and phosphorylated forms have been reported. The 3D-structures highlighted the features that undergo substantial changes and play a key role in the activati
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses FGFR3 cancer mutations, indicating that the variants K650, R669, N540, and I538 are associated with cancer, suggesting their role in tumor development or progression.
Gene→Variant (gene-first): 2263:I538 2261:K650 2261:N540 2261:R669
Genes: 2263 2261
Variants: I538 K650 N540 R669
Comparison of positions mutated in bone dysplasia in all FGFRs with those reported for FGFR3 in cancer (Figure 1B, bottom) highlighted common residues including I538, N540, K650 and R669. With respect to the secondary st
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 6
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 2261:G697 2263:I538 2261:K650 2261:N540 2261:R669
Genes: 2261 2263
Variants: G697 I538 K650 N540 R669
It has been previously highlighted that a number of cancer mutations, in particular in FGFR2 and FGFR3, have also been described in various developmental syndromes such as bone dysplasia. Positions mutated in FGFR3 in th
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 5
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses mutations in FGFR3, including K650 and N540, in the context of developmental syndromes such as bone dysplasia, indicating their association with specific disease states. Oncogenic: The mention of FGFR3 mutations, including K650 and N540, being prevalent in bladder cancer suggests that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2261:K650 2261:N540 2261:N540K
Genes: 2261
Variants: K650 N540 N540K
The intracellular portion (residues 397-806 for FGFR3) comprises the juxtamembrane region, KD and C-terminal regions. The number of observed mutations at each residue within the intracellular portion of FGFR3 was compile
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 4
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses frequently mutated positions in FGFR3, specifically K650, G697, and N540, indicating their involvement in cancer, which suggests they contribute to tumor development or progression. Functional: The passage describes the specific amino acid replacements at the mutated positions, indicating alterations in molecular function related to FGFR3, which can affect its activity in cancer.
Gene→Variant (gene-first): 2261:G697 2261:G697C 2261:K650 2261:N540
Genes: 2261
Variants: G697 G697C K650 N540
To elucidate the functional consequences of ETV6 alterations, we performed luciferase reporter assays using an ETV6-responsive reporter construct (pGL2-754TR) derived from the stromelysin-1 gene. In line with the role of
[Paragraph-level] PMCID: PMC3244026 Section: RESULTS PassageIndex: 9
Evidence Type(s): Functional, Diagnostic
Justification: Functional: The passage discusses how the ETV6 mutants (V345fs, N356fs, Y103fs, S105fs) are functionally inactive and lack transcriptional repression activity, indicating that these variants alter molecular function. Diagnostic: The passage mentions that ETV6-mutated cases have a characteristic gene expression signature and that all ETV6 mutant T-ALL samples were CD33 positive, suggesting that these variants are associated with a specific disease subtype.
Gene→Variant (gene-first): 2120:N356fs 2120:S105fs 2120:V345fs 2120:Y103fs
Genes: 2120
Variants: N356fs S105fs V345fs Y103fs
The ETV6 tumor suppressor gene is frequently translocated in lymphoid and myeloid hematopoietic tumors and encodes a transcriptional repressor with an N-terminal pointed (PNT) homodimerization domain and a C-terminal ETS
[Paragraph-level] PMCID: PMC3244026 Section: RESULTS PassageIndex: 8
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage describes how N-terminal and C-terminal truncating mutations in the ETV6 gene alter the expression of truncated protein products, indicating a change in molecular function. Oncogenic: The context of the mutations being associated with hematopoietic tumors suggests that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2120:N356fs 2120:S105fs 2120:V345fs 2120:Y103fs
Genes: 2120
Variants: N356fs S105fs V345fs Y103fs
NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) was originally described as a somatic variant in six RCCs without VHL inactivation, in three cases within The Cancer Genome Atlas and subsequently in five cases from the Memorial S
[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 9
Evidence Type(s): Oncogenic, Diagnostic
Justification: Oncogenic: The passage describes the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant as a somatic variant found in renal cell carcinomas (RCCs) and indicates its role in VHL-independent renal tumorigenesis, supporting its contribution to tumor development. Diagnostic: The passage discusses the search for germline ELOC variants in individuals with a VHL-like phenotype and indicates that the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant was absent in these individuals, suggesting its potential use in defining or excluding a disease or subtype.
Gene→Variant (gene-first): 3091:c.236A>G 6921:c.261_272del 5979:c.274G>A 6921:c.311T>A 3855:c.74A>T 3855:p.Asp25Val 7409:p.Glu92Lys 6921:p.Leu104Gln 6921:p.Thr88_Pro91del 3091:p.Tyr79Cys
Genes: 3091 6921 5979 3855 7409
Variants: c.236A>G c.261_272del c.274G>A c.311T>A c.74A>T p.Asp25Val p.Glu92Lys p.Leu104Gln p.Thr88_Pro91del p.Tyr79Cys
ELOC c.236A>G (p.Tyr79Cys) variation in human disease
[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 8
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 3091:c.236A>G 3091:p.Tyr79Cys
Genes: 3091
Variants: c.236A>G p.Tyr79Cys
Microarray-based comparative genomic hybridization (aCGH) performed on the DNA pair extracted from the proband's right RCC and blood showed evidence of monosomy for chromosomes 8, 21 and 22 and no somatic alterations wer
[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 6
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 3091:236A>G 3091:c.236A>G 3091:p.Tyr79Cys
Genes: 3091
Variants: 236A>G c.236A>G p.Tyr79Cys
Routine diagnostic testing by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) for a germline VHL variant showed no abnormality, and after informed written consent, the proband and her parent
[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 5
Evidence Type(s): Diagnostic, Functional
Justification: Diagnostic: The passage discusses the identification of a de novo missense variant in ELOC and its validation in the proband, indicating its potential role in defining or confirming a genetic condition. Functional: The passage describes the critical role of the Tyr79 residue in forming a hydrogen bond within the pVHL alpha domain, suggesting that the variant alters molecular function.
Gene→Variant (gene-first): 3091:Tyr79 3091:Y79 3091:c.236A>G 3091:p.Tyr79Cys
Genes: 3091
Variants: Tyr79 Y79 c.236A>G p.Tyr79Cys
Across the entire study, 2 patients with K-RAS mutations (endometrial cancer [20 mg/d] and codon 12-mutated NSCLC [30 mg/d], n = 1 each) had confirmed responses, which resulted in an ORR of 3.4%; 32 patients (54.2%) with
[Paragraph-level] PMCID: PMC7325368 Section: RESULTS PassageIndex: 11
Evidence Type(s): Predictive, Diagnostic, Oncogenic
Justification: Predictive: The passage discusses the confirmed responses and stable disease (SD) in patients with K-RAS mutations, including G13D, indicating a correlation with treatment response. Diagnostic: The mention of K-RAS mutations, including G13D, in the context of specific cancer types (endometrial cancer and NSCLC) suggests its role in classifying or defining these diseases. Oncogenic: The reference to K-RAS mutations, including G13D, contributing to tumor development in specific cancer types supports the classification of this variant as oncogenic.
Gene→Variant (gene-first): 3845:G13D
Genes: 3845
Variants: G13D
Patients with B-RAF and K-RAS mutations from both phases had responses (Table 3). Among patients with B-RAF mutations, 8 (15.1%) of 53 achieved PR, including 1 patient with melanoma who received prior RAF inhibitor thera
[Paragraph-level] PMCID: PMC7325368 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the responses of patients with B-RAF mutations to therapy, indicating a correlation between the B-RAFV600E variant and treatment response, which is characteristic of predictive evidence. Oncogenic: The B-RAFV600E variant is mentioned in the context of patients with B-RAF-mutated tumors, suggesting its role in tumor development or progression, which aligns with oncogenic evidence.
Gene→Variant (gene-first): 673:B-RAFV600E
Genes: 673
Variants: B-RAFV600E
In the retrospective cohort (n = 102), 14 samples were excluded due to insufficient coverage. Among the remaining 88 cases, 45 cases had mutations: 27 PIK3CA, 11 TEK (one with two mutations in cis, TEK: c.[2690A > G; c.2
[Paragraph-level] PMCID: PMC6594036 Section: RESULTS PassageIndex: 8
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 7010:2690A > G 3845:Arg918Cys 7010:Tyr897Cys 7010:c.2752A > G
Genes: 7010 3845
Variants: 2690A > G Arg918Cys Tyr897Cys c.2752A > G
The BRCA1 tumor suppressor gene encodes a multi-domain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks (DSB), which i
[Paragraph-level] PMCID: PMC7612117 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The variant p.L1363P is shown to disrupt the interaction with PALB2 and leads to the development of mammary tumors, indicating its contribution to tumor development. Predictive: The passage states that Brca1 p.L1363P mammary tumors are responsive to cisplatin and PARP inhibition, suggesting a correlation with treatment response.
Gene→Variant (gene-first): 7158:p.L1363P
Genes: 7158
Variants: p.L1363P
We examined Mig-6 expression in PC9 cells harboring the EGFR exon 19 deletion and PC9/GR cells, which have EGFR-TKI resistance with an acquired T790M mutation. Western blotting and immunofluorescence analyses showed that
[Paragraph-level] PMCID: PMC7302243 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the acquired T790M mutation in the context of EGFR-TKI resistance, indicating a correlation with treatment resistance. Oncogenic: The T790M mutation is described as contributing to EGFR-TKI resistance, which is a characteristic of tumor progression in the context of cancer.
Gene→Variant (gene-first): 1956:T790M
Genes: 1956
Variants: T790M
Activation of p110beta/p85alpha-nicSH2 and p110delta/p85alpha-nicSH2 complexes by phosphopeptide also induces lipid binding (Figure 5a). This is in agreement with the recent report for p110delta in a complex with full-le
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 24
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the variant H1047L alters the lipid binding capabilities of the p110alpha isoform, indicating a change in molecular function.
Gene→Variant (gene-first): 5290:H1047 5290:H1047L
Genes: 5290
Variants: H1047 H1047L
The p85alpha nSH2 does not contact the lipid binding elements in the kinase C-lobe (Figure 4a) but appears to control their access to membrane (Figure 3f-j). This suggests the activation mechanism by nSH2 to be allosteri
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 22
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the H1047R variant leads to a global conformational change in the p110alpha/p85alpha structure, suggesting that it alters molecular function and potentially impacts activity. Oncogenic: The context implies that the H1047R variant contributes to tumor development or progression through its role in altering the conformational dynamics of the kinase, which is relevant in cancer biology.
Gene→Variant (gene-first): 5290:H1047R
Genes: 5290
Variants: H1047R
For non-kinase domain mutants, the nature of the effects of hydrophobicity is not immediately obvious. Disruption of the C2-iSH2 (C420R and p85alpha-N564D) or the C2/helical-nSH2 contacts (E545K) could expose hydrophobic
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 20
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the variants C420R and N564D alter the molecular interactions within the C2 domain, suggesting changes in lipid binding capabilities, which indicates an alteration in biochemical function.
Gene→Variant (gene-first): 5290:C420 5290:C420R 5290:E545K 5295:N345 5295:N564 5295:N564D
Genes: 5290 5295
Variants: C420 C420R E545K N345 N564 N564D
Despite their different chemical properties, the kinase domain mutants, H1047L, H1047R and G1049R, exhibit similarly high levels of hydrophobic binding to neutral lipids, and electrostatic binding to PS/PtdIns(4,5)P2-con
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 19
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the variants G1049R, H1047L, and H1047R alter binding properties to lipids, indicating a change in molecular function related to lipid binding upon activation.
Gene→Variant (gene-first): 5290:G1049R 5290:H1047L 5290:H1047R
Genes: 5290
Variants: G1049R H1047L H1047R
There is a pattern correlating the location of the mutations with their hydrophobic component of lipid binding (Figure 3j): non-kinase domain mutants (C420R, E545K and p85alpha-N564D) display high levels of hydrophobic i
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 18
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the mutations (C420R, E545K, and N564D) alter the hydrophobic interaction with neutral lipids, indicating a change in molecular function related to lipid binding.
Gene→Variant (gene-first): 5290:C420R 5290:E545K 5295:N564D
Genes: 5290 5295
Variants: C420R E545K N564D
Overall, there is a strong correlation between lipid kinase activity and lipid binding (Figure 3i,j, total lipid binding on Fc4 is shown in Supplementary Figure S3), underscoring enhanced lipid binding as a general mecha
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 17
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the E545K variant alters lipid kinase activity and lipid binding, indicating a change in molecular function.
Gene→Variant (gene-first): 5290:E545K
Genes: 5290
Variants: E545K
To gain a broader view of the effects of cancer-linked mutations, we studied seven mutations that have previously been characterized to be activating. They cover three structurally distinct regions (Figure 3a-c), namely,
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 16
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses mutations that are characterized as activating, indicating that they contribute to tumor development or progression.
Gene→Variant (gene-first): 5290:C420R 5290:E545K 5290:G1049R 5290:H1047L 5290:H1047R 5290:M1043I 5295:N564D
Genes: 5290 5295
Variants: C420R E545K G1049R H1047L H1047R M1043I N564D
Using PtdIns(4,5)P2-containing liposomes, no kinase activity could be detected for three engineered kinase domain mutants: (i) the activation loop mutant R949D, (ii) the kinase helix kalpha12 deletion mutant (Deltacterm)
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 14
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the K942Q and R949D variants alter molecular function, specifically their effects on kinase activity and lipid binding, indicating changes in biochemical properties.
Gene→Variant (gene-first): 5294:K942Q 5294:R949D
Genes: 5294
Variants: K942Q R949D
To test whether lipid binding forms the basis of p110 activation, we compared lipid kinase with lipid binding activities for three sets of p110alpha/p85alpha complexes: SH2 deletions in p85alpha, engineered mutations in
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 9
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the D915N mutation in the context of its role in lipid binding and activation of p110alpha, indicating that it alters molecular function related to protein activity. Oncogenic: The mention of "cancer-linked mutations" suggests that the D915N variant is associated with tumor development or progression, as it is discussed in the context of p110alpha, which is implicated in cancer.
Gene→Variant (gene-first): 5290:D915N
Genes: 5290
Variants: D915N
Deletion of helix kalpha12 in Vps34, p110beta and p110delta abrogated lipid kinase activity and lipid binding. This region is also of functional importance for p110alpha (see below). Deletion of kalpha12 in Vps34 and in
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 7
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the deletion of residues 1051-1068 alters the lipid kinase activity and ATPase activity of p110alpha, indicating a change in molecular function.
Gene→Variant (gene-first): 5290:deletion of residues 1051-1068
Genes: 5290
Variants: deletion of residues 1051-1068
Our structure is for the WT p110alpha, but the kinase C-terminal tail more closely resembles those in the structures of the oncogenic mutant H1047R p110alpha/p85alpha-niSH2, than that in the WT apo p110alpha/p85alpha-iSH
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 6
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the oncogenic mutant H1047R p110alpha, indicating that this variant is associated with tumor development or progression, particularly in the context of its structural characteristics compared to the wild-type. Functional: The passage describes how the H1047R variant affects the conformation of the C-terminal tail and its interactions, suggesting alterations in molecular or biochemical function related to the protein's structure.
Gene→Variant (gene-first): 5290:H1047R
Genes: 5290
Variants: H1047R
A crystal structure of mouse WT p110alpha in complex with human p85alpha niSH2 fragment and the p110beta/p110delta selective inhibitor PIK-108 has been determined and refined to 3.5 A (Rwork/Rfree=0.184/0.228) (acronyms
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 3
Evidence Type(s): Functional
Justification: Functional: The passage discusses key conserved activation loop residues K942 and R949 and their importance in recognizing the substrate, indicating that these variants alter molecular function related to substrate binding.
Gene→Variant (gene-first): 5294:K942 5294:R949
Genes: 5294
Variants: K942 R949
Somatic missense mutations in PIK3CA, which encodes the p110alpha catalytic subunit of phosphoinositide 3-kinases (PI3Ks), occur frequently in human cancers. Activating mutations spread across multiple domains, some of w
[Paragraph-level] PMCID: PMC3378484 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses somatic missense mutations in PIK3CA that contribute to increased kinase activities and lipid binding, indicating their role in tumor development or progression. Functional: The passage describes how specific mutations alter the molecular function of the p110alpha protein, including increased basal activity and lipid binding, which are indicative of changes in biochemical function.
Gene→Variant (gene-first): 5290:C420R 5290:E545K 5290:G1049R 5290:H1047L 5290:H1047R 5290:M1043I 5295:N564D
Genes: 5290 5295
Variants: C420R E545K G1049R H1047L H1047R M1043I N564D
This analysis reported a mutation in BRAF p.V600E c.1799T > A (8819 reads out of a total 16,712 sequence reads for an allele frequency of 52.77). After multidisciplinary discussion at our molecular tumour board, it was d
[Paragraph-level] PMCID: PMC4239128 Section: RESULTS PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the potential vulnerability of the malignancy to BRAF inhibition, indicating a correlation between the BRAF p.V600E mutation and response to therapy with dabrafenib and trametinib. Oncogenic: The BRAF p.V600E mutation is implicated in the malignancy's development and progression, as it is associated with the treatment approach and the observed tumor response to therapy.
Gene→Variant (gene-first): 673:1799T > A 673:p.V600E
Genes: 673
Variants: 1799T > A p.V600E
Our data suggest that some clinically relevant D835 mutants retain sensitivity to type II inhibitors at clinically achievable drug concentrations and propose a molecular mechanism for differences in sensitivity for indiv
[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 8
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the sensitivity of D835 mutants to type II inhibitors, indicating a correlation with treatment response, which aligns with predictive evidence. Oncogenic: The mention of D835 mutations and their role in mediating resistance and sensitivity to FLT3 TKIs suggests that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2322:D835 2322:D835N/E
Genes: 2322
Variants: D835 D835N/E
Unlike the mutations discussed above, the models of the moderately resistant D835H mutation based each of the two template structures differ from each other. We assume the model based on the quizartinib template is more
[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the D835H mutation's resistance to type II inhibitors, indicating a correlation with treatment response and sensitivity to specific therapies. Functional: The passage describes how the D835H mutation alters the binding mode and hydrogen bond formation, indicating a change in molecular function related to inhibitor interaction.
Gene→Variant (gene-first): 2322:D835H
Genes: 2322
Variants: D835H
The most highly resistant mutants (D835Y/V/I/F) are large and bulky hydrophobic amino acid residues. In addition to an inability to hydrogen bond with S838, these large side chains are predicted to be sterically incompat
[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 6
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the D835Y/V variant alters molecular interactions and structural compatibility, indicating a change in biochemical function related to steric hindrance and hydrogen bonding. Oncogenic: The mention of "highly resistant mutants" suggests that the D835Y/V variant contributes to tumor development or progression by conferring resistance, which is characteristic of oncogenic behavior.
Gene→Variant (gene-first): 2322:D835Y/V
Genes: 2322
Variants: D835Y/V
The most sensitive mutants (D835E/N) are characterized by the predicted preservation of the hydrogen bond between D835 and S838 based on models utilizing both the apo and holo structures as templates. Side chains of the
[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 5
Evidence Type(s): Functional, Predictive
Justification: Functional: The passage discusses how the D835E/N mutations alter molecular interactions, specifically the formation of hydrogen bonds and the conservation of the alpha-helix structure, which affects inhibitor binding. Predictive: The passage indicates that the D835E/N variants are associated with sensitivity to type II inhibitors, suggesting a correlation with treatment response.
Gene→Variant (gene-first): 2322:D835 2322:D835E/N
Genes: 2322
Variants: D835 D835E/N
It is not straightforward to rationalize the effect of mutations near or in the short alpha-helix on the distant drug-binding active site. Nevertheless, it has been suggested that the short alpha-helix, which is part of
[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 4
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the correlation of D835 mutations with resistance to type II inhibitors, indicating a relationship between the variant and treatment response. Functional: The passage describes the impact of D835 mutations on the short alpha-helix and its potential effect on the drug-binding site, suggesting an alteration in molecular function related to drug interaction.
Gene→Variant (gene-first): 2322:D835
Genes: 2322
Variants: D835
Type II inhibitors bind to the conformation coupled to the DFG-out position of the kinase AL (residues 829-856 in FLT3). As previously noted, D835 is predicted to play a critical role in the stabilization of the DFG-out
[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 3
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the D835 variant alters the molecular function of the kinase by stabilizing the DFG-out conformation and forming interactions that affect the structure of the alpha-helix.
Gene→Variant (gene-first): 2322:D835
Genes: 2322
Variants: D835
We profiled all D835 substitutions previously reported to cause FLT3 TKI resistance in patients, as well as D835 mutations occurring in patients as cataloged in the Sanger COSMIC database or the Cancer Genome Atlas. Inhi
[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how various D835 substitutions correlate with resistance to FLT3 inhibitors, indicating their predictive value regarding treatment response. Oncogenic: The D835 mutations are reported to cause resistance in patients, suggesting that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2322:D835 2322:D835A/E 2322:D835H 2322:D835V/Y
Genes: 2322
Variants: D835 D835A/E D835H D835V/Y
In both patients with a clinical diagnosis of FAO (patients 2 and 3), targeted deep sequencing analysis led to the identification of a PIK3CA mutation in primary fibroblasts samples only. Specifically, a c.3140 A>G [p.H1
[Paragraph-level] PMCID: PMC4411002 Section: RESULTS PassageIndex: 16
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the identification of PIK3CA mutations in patients with a clinical diagnosis of FAO, indicating that these variants are used to define or confirm the disease in these patients. Oncogenic: The PIK3CA mutations mentioned are somatic variants identified in primary fibroblasts, which suggests they contribute to tumor development or progression in the context of the patients' disease.
Gene→Variant (gene-first): 5294:3140 A>T 5290:c.3140 A>G 5290:c.3140 A>T 5290:p.H1047L 5290:p.H1047R
Genes: 5294 5290
Variants: 3140 A>T c.3140 A>G c.3140 A>T p.H1047L p.H1047R
This approach confirmed the presence of the c.241 G>A [p.E81K] mutation in the right and left leg biopsies of patient 1, with mutant allele frequencies of 9% and 21.5%, respectively (Fig 1d).
[Paragraph-level] PMCID: PMC4411002 Section: RESULTS PassageIndex: 15
Evidence Type(s): Diagnostic
Justification: Diagnostic: The passage confirms the presence of the c.241 G>A [p.E81K] mutation in the biopsies of a patient, indicating its role in defining or confirming the disease in that individual.
Gene→Variant (gene-first): 5290:c.241 G>A 5290:p.E81K
Genes: 5290
Variants: c.241 G>A p.E81K
Mutational analysis of PIK3CA exons and adjacent intronic regions was performed by Sanger sequencing methods on genomic DNA isolated from blood samples, tissue biopsies, and cultured dermal fibroblasts. No pathogenic var
[Paragraph-level] PMCID: PMC4411002 Section: RESULTS PassageIndex: 12
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the identification of the c.241 G>A [p.E81K] mutation in a specific patient, indicating its association with the patient's condition and its absence in the patient's parents, which suggests its role in defining or confirming a disease. Oncogenic: The mention of the mutation being detected in various tissues of the patient, particularly in the context of a mutational analysis, implies its potential contribution to tumor development or progression.
Gene→Variant (gene-first): 5290:c.241 G>A 5290:p.E81K
Genes: 5290
Variants: c.241 G>A p.E81K
To identify molecules that could be pharmacologically targeted in NF1Mut melanomas, we first established 32 STCs from subcutaneous, lymph node, and brain metastases of 30 patients with melanoma (Fig. 1A; Supplementary Ta
[Paragraph-level] PMCID: PMC12221223 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the identification of mutational profiles in melanoma, specifically mentioning that C>T transitions are characterized as cutaneous melanoma-defining features, which indicates a role in classifying or defining the disease. Oncogenic: The mention of C>T transitions as part of the mutational profile in melanoma suggests that these somatic variants contribute to tumor development or progression, particularly in the context of melanoma.
Gene→Variant (gene-first): 4763:C>T
Genes: 4763
Variants: C>T
Pilomyxoid astrocytomas are an aggressive subtype of astrocytoma, not graded by WHO, frequently located in hypothalamic/chiasmatic regions, affecting diencephalic structures, and characterized by shorter survival and hig
[Paragraph-level] PMCID: PMC8077124 Section: ABSTRACT PassageIndex: 10
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The variant p.K656E is described as an activating and transforming mutation, indicating its role in tumor development or progression. Predictive: The variant p.V561M is mentioned as imparting resistance to FGFR inhibitors, suggesting its correlation with treatment response.
Gene→Variant (gene-first): 2260:p.K656E 2260:p.V561M
Genes: 2260
Variants: p.K656E p.V561M
Similar variant allele frequencies of FGFR1 p.K656E and FGFR1 p.V561M mutations in our patient's tumor suggest that these mutations may have occurred at similar time points. Use of FGFR inhibitors in addition to STAT3 or
[Paragraph-level] PMCID: PMC8077124 Section: ABSTRACT PassageIndex: 9
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the potential use of FGFR inhibitors in combination with other treatments, indicating a correlation with therapy response. Oncogenic: The mention of mutations in the context of a tumor suggests that the variants may contribute to tumor development or progression.
Gene→Variant (gene-first): 2260:p.K656E 2260:p.V561M
Genes: 2260
Variants: p.K656E p.V561M
We identified two somatic activating missense mutations affecting FGFR1, including FGFR1 p.K656E and FGFR1 p.V561M. While the former is a known hotspot mutation that is both activating and transforming, the latter has be
[Paragraph-level] PMCID: PMC8077124 Section: ABSTRACT PassageIndex: 7
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The passage describes p.K656E as a known hotspot mutation that is activating and transforming, indicating its role in tumor development or progression. Predictive: The passage mentions that p.V561M is described as a gatekeeper mutation imparting resistance to FGFR inhibitors, which correlates with treatment response.
Gene→Variant (gene-first): 2260:p.K656E 2260:p.V561M
Genes: 2260
Variants: p.K656E p.V561M
Finally, patient UPN 2 was characterized by TKD D835Y mutation (43%) and a small ITD mutated clone (revealed only by UDS analysis, 0,4%) at diagnosis. After two months of conventional chemotherapy treatment (3+7 schedule
[Paragraph-level] PMCID: PMC4741605 Section: RESULTS PassageIndex: 20
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of the patient to chemotherapy treatment and how the presence of the D835Y mutation correlates with the patient's relapse, indicating its potential role in therapeutic decisions. Oncogenic: The D835Y mutation is described as a mutation that contributes to the tumor's behavior, particularly in the context of the patient's relapse and the increase in the mutated clone's percentage.
Gene→Variant (gene-first): 2322:D835Y
Genes: 2322
Variants: D835Y
Patient UPN 5 showed resistance to conventional induction chemotherapy (Cytarabine and Idarubicine). UDS analysis revealed a progressive expansion of the ITD+ clone over time (from 3,78% at diagnosis to 12,3% two months
[Paragraph-level] PMCID: PMC4741605 Section: RESULTS PassageIndex: 19
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the resistance of the D835Y variant to conventional induction chemotherapy and indicates that the treatment successfully inhibited the D835Y mutated clone, suggesting a correlation with treatment response. Oncogenic: The D835Y variant is mentioned in the context of tumor progression and its behavior in response to treatment, indicating its role in tumor development or progression.
Gene→Variant (gene-first): 2322:D835Y
Genes: 2322
Variants: D835Y
Patient UPN 4 received conventional induction chemotherapy and after an initial expansion of the FLT3 ITD+ clone, he achieved a complete morphological remission at the end of a "3+7" induction schedule. At molecular leve
[Paragraph-level] PMCID: PMC4741605 Section: RESULTS PassageIndex: 18
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage states that the mutations D839G and D835H are able to confer resistance to Sorafenib treatment, indicating a correlation between these variants and treatment response. Oncogenic: The presence of the D839G and D835H mutations is associated with the evolution of the FLT3 ITD+ clone and suggests a role in tumor development or progression, particularly in the context of acute myeloid leukemia (AML).
Gene→Variant (gene-first): 2322:D835H 2322:D839G
Genes: 2322
Variants: D835H D839G
Patient UPN 3 received best supportive therapy (BST). The ITD+ clone progressively increased (from 1,34% at diagnosis to 29,4% after 14 months of follow-up), along with the appearance of a minor ITD+ clone (0,6%) and two
[Paragraph-level] PMCID: PMC4741605 Section: RESULTS PassageIndex: 17
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the patient's response to the FLT3 inhibitor AC220-002, indicating that the presence of the D835Y and D839G variants may correlate with the patient's treatment response. Oncogenic: The D835Y and D839G variants are mentioned in the context of their abundance in the patient's sample, suggesting their potential role in tumor development or progression as part of the FLT3 mutation landscape.
Gene→Variant (gene-first): 2322:D835Y 2322:D839G
Genes: 2322
Variants: D835Y D839G
Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, anaplastic lymphoma kinase (ALK) inhibitors have become important treatments for a subset of patients with lung c
[Paragraph-level] PMCID: PMC9398166 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how the G1202R and L1196M mutations are major resistance mechanisms to ALK inhibitors, indicating that these variants correlate with resistance to specific therapies. Oncogenic: The G1202R and L1196M mutations are described as resistance mechanisms that contribute to tumor progression, particularly in the context of ALK inhibitors, suggesting their role in oncogenesis.
Gene→Variant (gene-first): 238:G1202R 238:L1196M
Genes: 238
Variants: G1202R L1196M
In order to assess if oncogenic BRAF signaling may induce venetoclax resistance, we overexpressed mutated BRAF (p.V600E) in a venetoclax-sensitive cell line OCI-LY19 (Fig. 3a). Exome sequencing of this cell line revealed
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 16
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how the BRAFV600E variant correlates with venetoclax resistance, indicating a relationship between the variant and treatment response. Oncogenic: The passage describes the overexpression of the mutated BRAF (p.V600E) in a cell line, which is associated with increased resistance to venetoclax, suggesting that this somatic variant contributes to tumor progression.
Gene→Variant (gene-first): 673:BRAFV600E 673:p.V600E 7157:p.W110*
Genes: 673 7157
Variants: BRAFV600E p.V600E p.W110*
Finally, case C586 showed a remarkable pattern of convergent evolution (Fig. 2d). We found two SF3B1 mutations (c.1996A > C; p.K666Q and c.1997A > C; p.K666T) affecting the same codon, but evolved in two independent clon
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 14
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the SF3B1 mutations in the context of venetoclax exposure and resistance, indicating a correlation between these variants and treatment response. Oncogenic: The SF3B1 mutations are described as evolving during treatment and being selected for during venetoclax therapy, suggesting their role in tumor development or progression.
Gene→Variant (gene-first): 23451:c.1996A > C 23451:c.1997A > C 23451:p.K666Q 23451:p.K666T
Genes: 23451
Variants: c.1996A > C c.1997A > C p.K666Q p.K666T
Patient C548 showed a divergent evolutionary path of two branches (Fig. 2c). One branch (subclone C3 and C4) was selected during venetoclax therapy. This branch harbored a homozygous loss of CDKN2A/B, and mutations in BR
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the selection of specific mutations (including p.K601E and p.Q547fs) during venetoclax therapy, indicating a correlation with treatment response. Oncogenic: The mutations p.K601E and p.S321fs are described as contributing to tumor development, as they are retained in the clonal evolution of the cancer during relapse.
Gene→Variant (gene-first): 673:p.K601E 330:p.Q547fs 58508:p.S321fs
Genes: 673 330 58508
Variants: p.K601E p.Q547fs p.S321fs
To gain insight into the clonal evolution towards therapy resistance, we inferred subclonal populations and reconstructed phylogenetic trees (see Methods). Intriguingly, we observed a wide spectrum of evolutionary dynami
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the involvement of BTG1 mutations (p.E46K and p.Q36H) in the resistance to venetoclax treatment, indicating a correlation between these variants and treatment response. Oncogenic: The passage describes the BTG1 mutations as being involved in the clonal evolution towards therapy resistance, suggesting that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 7157:p.E46K 694:p.Q36H
Genes: 7157 694
Variants: p.E46K p.Q36H
Recurrent genomic changes that evolved during venetoclax treatment were homozygous deletions affecting CDKN2A/B in three patients (C548, C577, C586) and BTG1 missense mutations in two cases (C577: p.Q36H; C789: p.E46K).
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 10
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses how damaging mutations in BTG1, including the p.Q36H and p.E46K variants, may provide a survival advantage to CLL cells under targeted BCL2-inhibition, indicating their contribution to tumor development or progression. Functional: The passage mentions that BTG1 has been shown to counteract cell proliferation, suggesting that the mutations may alter its molecular or biochemical function.
Gene→Variant (gene-first): 7157:p.E46K 694:p.Q36H
Genes: 7157 694
Variants: p.E46K p.Q36H
In line with previous findings patients responded to venetoclax therapy, even if TP53 was initially mutated in a bi-allelic fashion (5/8 patients). Two patients showed genome alterations that might qualify for further th
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 8
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The passage states that the BRAF (p.K601E) mutation was shown to be oncogenic and can be targeted by MEK inhibitors, indicating its role in tumor development or progression. Predictive: The mention of patients responding to venetoclax therapy, even with the presence of the BRAF mutation, suggests a correlation with treatment response, which aligns with predictive evidence.
Gene→Variant (gene-first): 673:p.K601E
Genes: 673
Variants: p.K601E
To understand whether trends observed in mouse tumors are also found in human disease, we next examined the HER2 and PIK3CA mutations in available TCGA RNA-seq data. We examined data available from 113 normal solid tissu
[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 25
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the association of the H1047R PIK3CA mutation with specific tumor subtypes, indicating its role in classifying or defining disease characteristics in human samples. Oncogenic: The H1047R PIK3CA mutation is mentioned in the context of tumor analysis, suggesting its contribution to tumor development or progression as it is examined alongside other mutations in cancer samples.
Gene→Variant (gene-first): 5290:H1047R
Genes: 5290
Variants: H1047R
Consistent with the proteomic data, pathway analysis showed that these genes were enriched for the PIK3-Akt-mTOR signaling pathway (Fig. 6B). The GSEA analysis showed that the mTOR pathway and the MYC target signature we
[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 22
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage indicates that the co-expression of the HER2V777L variant contributes to tumorigenesis by amplifying signaling pathways, suggesting its role in tumor development.
Gene→Variant (gene-first): 2064:V777L
Genes: 2064
Variants: V777L
We next examined gene expression changes using RNA sequencing. We established organoids from H, P, and HP mice tumors and normal mammary glands from WT littermate mice and performed RNA sequencing analysis on 16 independ
[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 20
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 2064:V777L
Genes: 2064
Variants: V777L
To further elucidate the function of the HER2V777L mutation in the HP mice tumor model, we then performed mass-spectrometry based phosphoproteomics on P and HP breast cancer organoids (Fig. 5C-5F). Organoids were prepare
[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 18
Evidence Type(s): Functional, Predictive
Justification: Functional: The passage discusses the phosphorylation levels of proteins in relation to the HER2V777L mutation, indicating that the variant alters molecular function, specifically in signaling pathways related to cancer. Predictive: The mention of increased phosphorylation of annexin A2 being associated with drug resistance suggests a correlation between the HER2V777L variant and resistance to therapy.
Gene→Variant (gene-first): 2064:V777L
Genes: 2064
Variants: V777L
In order to characterize the mechanism causing the rapid breast cancer growth in HP mice, we measured protein phosphorylation using proteomics. We examined the key signaling pathways using the Human/Mouse AKT Pathway Pho
[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 17
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the HER2V777L variant enhances cell proliferation by altering the phosphorylation of key proteins involved in the cell cycle, indicating a change in molecular function. Oncogenic: The evidence suggests that the HER2V777L variant contributes to tumor development and progression by promoting aggressive growth in the transgenic mouse model.
Gene→Variant (gene-first): 2064:V777L
Genes: 2064
Variants: V777L
To validate the results of the neratinib plus T-DXd in a second experimental model, we used the human breast cancer PDX, WHIM51, which has the same PIK3CA mutation and a HER2 activating mutation at the neighboring codon,
[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 15
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of the WHIM51 PDX model to the drug combination of neratinib plus T-DXd, indicating that the G776insYVMA and V777L mutations correlate with a significant tumor regression in response to this therapy. Oncogenic: The G776insYVMA and V777L mutations are associated with tumor regression in the context of breast cancer, suggesting that these somatic variants contribute to tumor development or progression as evidenced by their behavior in the experimental model.
Gene→Variant (gene-first): 2064:G776insYVMA 2064:V777L
Genes: 2064
Variants: G776insYVMA V777L
We hypothesized that the HER2V777L mutation plays a vital role in metastatic breast cancer. To test this, H, P and HP mice were examined for metastasis to the lung or liver. Metastasis were not seen in HP mice likely bec
[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 9
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the HER2V777L mutation's role in metastatic breast cancer, indicating that it contributes to tumor development and progression, particularly in the context of lung metastasis observed in transgenic mice. Functional: The passage implies that the HER2V777L mutation alters the behavior of breast tumor cells, as evidenced by the invasive phenotype observed in vitro and the specific uptake of the NIR-trastuzumab imaging agent in tumor sites.
Gene→Variant (gene-first): 2064:V777L
Genes: 2064
Variants: V777L
Lung metastases in HER2V777L transgenic mice and HP organoid transplant mice
[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 8
Evidence Type(s): Oncogenic
Justification: Oncogenic: The mention of "Lung metastases in HER2V777L transgenic mice" suggests that the V777L variant contributes to tumor development or progression in a model organism, indicating its oncogenic potential.
Gene→Variant (gene-first): 2064:V777L
Genes: 2064
Variants: V777L
We isolated breast organoids from WT, H, P, HP mice (Fig. 2A) in order to obtain an enriched epithelial cell population. To assess the cellular migration and invasion signature of HER2V777L and PIK3CAH1047R breast epithe
[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses how the combination of HP mutations, including HER2V777L, promotes cancer cell invasion and migration, indicating a role in tumor development or progression. Functional: The passage describes the effects of the HER2V777L variant on cellular migration and invasion, suggesting that it alters molecular or biochemical functions related to these processes.
Gene→Variant (gene-first): 2064:V777L
Genes: 2064
Variants: V777L
Organoids derived from HER2V777L and PIK3CAH1047R tumors.
[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 6
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 2064:V777L
Genes: 2064
Variants: V777L
We previously reported the development of a novel transgenic mouse that conditionally expresses the human HER2 V777L cDNA (abbreviated as "H"), which is inserted into the Rosa26 locus using TALEN-based genome editing. Ou
[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 3
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage describes the PIK3CA H1047R variant as a gain-of-function allele and activating mutation commonly found in human breast cancers, indicating its role in tumor development or progression.
Gene→Variant (gene-first): 5290:H1047R 2064:V777L
Genes: 5290 2064
Variants: H1047R V777L
Tumor formation in mice with HER2V777L and PIK3CAH1047R
[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 2
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage indicates that the HER2V777L variant is involved in tumor formation in mice, suggesting it contributes to tumor development or progression.
Gene→Variant (gene-first): 2064:V777L
Genes: 2064
Variants: V777L
As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimeritnib is the standard treatment for patients with non-small cell lung cancer harboring the EGFR T790M mutation; however
[Paragraph-level] PMCID: PMC5792548 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Diagnostic, Oncogenic
Justification: Predictive: The passage discusses the EGFR T790M mutation in the context of treatment response to osimeritinib and the development of resistance, indicating a correlation with therapy outcomes. Diagnostic: The passage states that the EGFR T790M mutation is used to identify patients with non-small cell lung cancer who are eligible for treatment with osimeritinib, thus classifying it as a diagnostic marker. Oncogenic: The EGFR T790M mutation is described as contributing to resistance in lung cancer, which implies its role in tumor progression and development.
Gene→Variant (gene-first): 1956:T790M
Genes: 1956
Variants: T790M
Treatment with TK inhibitors rescues the phenotype induced by EPHB4-V871I in NB cell lines
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 16
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage indicates that treatment with TK inhibitors has a positive effect on the phenotype induced by the EPHB4-V871I variant, suggesting a correlation with response to therapy. Oncogenic: The mention of the EPHB4-V871I variant inducing a phenotype in neuroblastoma (NB) cell lines implies that it contributes to tumor development or progression.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
We then tried to study possible targets of EPHB4. We studied three EPHB4 downstream target genes by analysing the mRNA levels of: VEGF, c-RAF and CDK4 genes by qRt-PCR. All three of these genes showed significantly highe
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 15
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the expression levels of downstream target genes and affects the phosphorylation status of the ERK1-2 pathway, indicating a change in molecular function.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
EPHB4-V871I increases the expression of some target genes and enhance the phosphorylation of ERK1-2 pathway
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 14
Evidence Type(s): Functional
Justification: Functional: The variant V871I alters molecular function by increasing the expression of target genes and enhancing the phosphorylation of the ERK1-2 pathway.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
We further analysed the anchorage-independent growth of EPHB4-MUT by colony formation assay in soft agar. EPHB4-V871I showed an increased number of colonies compared with WT and EV in both cell lines (Figure 4B).
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 13
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The variant EPHB4-V871I is associated with increased anchorage-independent growth, indicating its contribution to tumor development or progression as demonstrated by the colony formation assay. Functional: The passage describes the effect of the EPHB4-V871I variant on cellular behavior, specifically its impact on colony formation, which suggests an alteration in molecular or biochemical function.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
We further analysed the migration properties of EPHB4 mutant clone by two-dimensional migration experiments. EPHB4-V871I showed an increased number of migrating cells compared with EV and EPHB4-WT in both cell lines (Fig
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 12
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the migration properties of cells, indicating a change in molecular function related to cell behavior.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
The migration potential was firstly assayed by wound-healing experiments demonstrating increased migration properties of EPHB4-V871I compared with both EV and EPHB4-WT in both cell lines (Figure 3C). Indeed, the percenta
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 11
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the migration properties of cells, indicating a change in molecular function related to cell behavior.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
Due to EPHB4 involvement in tumour angiogenesis, growth and metastasis, 21 we speculated on its potential regulation of cellular proliferation, cell migration and anchorage-independent growth in vitro. The proliferation
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 10
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the proliferation rate of cells, indicating a change in molecular or biochemical function. Oncogenic: The increased proliferation rate associated with the EPHB4-V871I variant suggests its contribution to tumor development or progression, as it is linked to cellular behaviors relevant to cancer.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
EPHB4-V871I affects proliferation and migration of NB cell lines
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 9
Evidence Type(s): Functional
Justification: Functional: The passage indicates that EPHB4-V871I alters the proliferation and migration of neuroblastoma (NB) cell lines, suggesting a change in molecular or biochemical function.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
In order to select the cell lines to perform the functional characterization of EPHB4-V871I variant, we firstly analysed the expression of EPHB4 in several NB cell lines. We divided our cell lines based on MYCN amplified
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 8
Evidence Type(s): Functional
Justification: Functional: The passage discusses the functional characterization of the EPHB4-V871I variant, specifically evaluating its expression and confirming that the mutation does not impair EPHB4 expression at the mRNA and protein level.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
The screening of kinome regions in NB cell lines resulted in 11 filtered mutations in eight genes. Here, we detected four additional ALK mutations. Of these, three were F1174L changes, and the other was the R1275Q change
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 5
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 238:F1174L 2260:N457K 238:R1275Q
Genes: 238 2260
Variants: F1174L N457K R1275Q
Interestingly, we found two mutations in EPHB4 (V871I) and in EphB6 (A417S) genes, both involved in axon guidance pathway. The variant V871I in the kinase domain of EPHB4 showed a high pathogenic score (Figure 1A and Tab
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 4
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses mutations in EPHB4 and EphB6 genes, indicating that the variant V871I is associated with a high pathogenic score, suggesting its contribution to tumor development or progression. Functional: The mention of the variant V871I being located in the kinase domain of EPHB4 implies a potential alteration in molecular or biochemical function related to its role in the axon guidance pathway.
Gene→Variant (gene-first): 4613:A417S 2050:V871I
Genes: 4613 2050
Variants: A417S V871I
We performed targeted sequencing of TK domains on a total of 45 NB normal-primary tumour matched pairs and 9 NB cell lines. All tumour samples were high-risk patients according to the COG Risk Group Classification System
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 3
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage indicates that the variant F1174L is a somatic mutation found in the ALK gene, which is associated with neuroblastoma (NB), suggesting its contribution to tumor development or progression.
Gene→Variant (gene-first): 238:F1174L
Genes: 238
Variants: F1174L
Kinome sequencing and identification of EPHB4-V871I mutation in NB patients
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 2
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
Consistent with our hierarchical clustering analysis, introduction of the R164Q mutation led to relatively few changes in gene expression or showed reduced pathway activation compared with the other mutants studied. Howe
[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 15
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the introduction of the R164Q mutation led to changes in gene expression and pathway activation, indicating that the variant alters molecular function. Oncogenic: The mention of the A146T, K117N, G13D, and Q61H mutations clustering together and influencing gene expression suggests that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 3845:A146T 3845:G13D 3845:K117N 3845:L19F 3845:Q61H 3845:R164Q
Genes: 3845
Variants: A146T G13D K117N L19F Q61H R164Q
To further compare and contrast the phenotypes associated with each of the K-Ras mutants, transcription-profiling experiments were carried out as described in Materials and Methods. Hierarchical clustering analysis revea
[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 13
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses transcription-profiling experiments and Ras GTPase assay data, indicating that the variants alter molecular or biochemical function, particularly in relation to their clustering and phenotypic characteristics. Oncogenic: The mention of the variants being associated with distinct phenotypes and their clustering suggests that these somatic mutations contribute to tumor development or progression.
Gene→Variant (gene-first): 3845:A146T 3845:G12C 3845:G12D 3845:G12V 3845:G13D 3845:K117N 3845:L19F 3845:R164Q
Genes: 3845
Variants: A146T G12C G12D G12V G13D K117N L19F R164Q
To assess which K-Ras mutations were in the active GTP-bound conformation, a Raf-1 binding assay was carried out as described in Materials and Methods. Raf-1 selectively binds GTP-bound Ras (rather than the inactive GDP-
[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 11
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how specific K-Ras mutations (G12V, L19F, K117N, A146T) are in the active GTP-bound conformation, indicating that these variants alter the molecular function of the K-Ras protein. Oncogenic: The mention of K-Ras mutations being in the active GTP-bound conformation suggests that these somatic variants contribute to tumor development or progression, as they are associated with active signaling pathways in cancer.
Gene→Variant (gene-first): 3845:A146T 3845:G12V 3845:K117N 3845:L19F 3845:R164Q
Genes: 3845
Variants: A146T G12V K117N L19F R164Q
Phenotypes associated with the various K-Ras mutations have previously not been systematically evaluated. To compare the transformation potential of the K-Ras mutants, therefore, NIH3T3 cells were transiently transfected
[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 9
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the transformation potential of various K-Ras mutations, indicating that these mutations contribute to tumor development as evidenced by the formation of foci in NIH3T3 cells after transfection. Functional: The study evaluates the molecular function of K-Ras mutations by assessing their ability to transform cells, which involves alterations in biochemical activity as demonstrated through focus formation assays.
Gene→Variant (gene-first): 3845:A146T 3845:G12D 3845:G12V 3845:G13D 3845:K117N 3845:L19F 3845:Q61H 3845:R164Q
Genes: 3845
Variants: A146T G12D G12V G13D K117N L19F Q61H R164Q
To identify additional K-Ras mutations, and to establish the relative frequencies of individual K-Ras mutations in human colorectal tumours, we used WAVE analysis followed by direct sequencing to screen the same tumour s
[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 4
Evidence Type(s): Diagnostic, Oncogenic, Functional
Justification: Diagnostic: The passage discusses the identification and relative frequencies of K-Ras mutations in human colorectal tumors, indicating their association with the disease. Oncogenic: The mention of K-Ras mutations, including the V600E mutation, suggests their contribution to tumor development or progression, as they are associated with increased mutation frequency in the Ras pathway. Functional: The passage notes the predicted localization of each mutation in the functional domains of the K-Ras protein, indicating an alteration in molecular function.
Gene→Variant (gene-first): 3845:A to C 3845:Ala to Thr 3845:Arg to Gln 3845:C to T 3845:G to A 3845:Lys to Asn 673:V600E 3845:aspartic acid residue at codon 173
Genes: 3845 673
Variants: A to C Ala to Thr Arg to Gln C to T G to A Lys to Asn V600E aspartic acid residue at codon 173
We have previously described K-Ras mutations at codons 12, 13 and 61 in a series of 106 unselected colorectal tumours. Our K-Ras mutation analysis was performed by direct sequencing of K-Ras exon 1 (codons 12 and 13) and
[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the detection of specific mutations in colorectal tumors, indicating their association with the disease, which supports their use in defining or classifying the disease. Oncogenic: The mention of mutations at codon 19 (G57T, Leu19Phe) and in B-Raf (V600E) suggests that these somatic variants may contribute to tumor development, as they are found in tumor samples.
Gene→Variant (gene-first): 673:G57T 3845:Leu19Phe 673:V600E
Genes: 673 3845
Variants: G57T Leu19Phe V600E
To determine if the synergy observed in vitro for PARPi-resistant cells translated to in vivo efficacy, SRA737 and PARPi combination therapy was tested in five HGSOC PDX models. Two HR competent CCNE1 amplified HGSOC PDX
[Paragraph-level] PMCID: PMC11253285 Section: RESULTS PassageIndex: 18
Evidence Type(s): Predictive, Prognostic
Justification: Predictive: The passage discusses the response to therapy involving SRA737 and PARP inhibitors (PARPi), indicating a correlation with treatment response in specific PDX models. Prognostic: The mention of a trending increase in survival with combination therapy compared to monotherapy suggests a correlation with disease outcome, although it did not reach statistical significance.
Gene→Variant (gene-first): 142:S4D
Genes: 142
Variants: S4D
PARPi-resistant JHOS4 PR (BRCA1MUT), PEO1 PR (BRCA2MUT), FUOV1, and OVCAR3 (CCNE1amp) cells were further tested for the mechanism by which SRA737 and PARPi synergistically inhibit tumor cell growth. Parental PEO1 and JHO
[Paragraph-level] PMCID: PMC11253285 Section: RESULTS PassageIndex: 15
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the mechanism by which SRA737 and PARPi synergistically inhibit tumor cell growth, indicating that the variant S3C is involved in tumor development or progression through its effects on cell lines with specific mutations. Functional: The passage describes how exposure to SRA737 results in specific phosphorylation changes in CHK1 and other proteins, indicating that the variant alters molecular or biochemical function related to tumor cell growth.
Gene→Variant (gene-first): 1111:S3C
Genes: 1111
Variants: S3C
To characterize the AR mechanism through RET fusions in EGFR-mutated NSCLC patients and their survival outcomes, we compared the PFS among patients treated with different EGFR-TKI regimens. However, no significant differ
[Paragraph-level] PMCID: PMC9441062 Section: RESULTS PassageIndex: 15
Evidence Type(s): Diagnostic, Prognostic
Justification: Diagnostic: The passage mentions that patients with L858R mutations were included in a refined cohort, indicating that this variant is used to classify or define a specific group of patients with EGFR mutations in NSCLC. Prognostic: The passage discusses the progression-free survival (PFS) of patients with specific mutations, including L858R, suggesting that this variant correlates with disease outcome independent of therapy.
Gene→Variant (gene-first): 1956:L858R
Genes: 1956
Variants: L858R
Despite their rarity, it is clear from previous studies that RTK fusions, such as RET rearrangements, are actionable resistance mechanisms to EGFR-TKIs. We aim to increase awareness of this emerging paradigm by comprehen
[Paragraph-level] PMCID: PMC9441062 Section: RESULTS PassageIndex: 14
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how the variants T790M, C797S/G, and L718V/Q are associated with resistance mechanisms to EGFR-TKIs, indicating their role in treatment response. Oncogenic: The variants mentioned are described as second-site mutations that contribute to resistance in the context of tumor development and progression in NSCLC.
Gene→Variant (gene-first): 1956:C797S/G 1956:L718V/Q 1956:T790M
Genes: 1956
Variants: C797S/G L718V/Q T790M
In the baseline cohort, 58.9% of patients were under 60 years (58.9% vs. 41.1%, P < 0.001), and the proportion of females was significantly higher than males (55.3% vs. 44.7%, P = 0.038, Table 1). Of the 71 patients with
[Paragraph-level] PMCID: PMC9441062 Section: RESULTS PassageIndex: 4
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage states that all 71 patients harbored baseline EGFR mutations, including specific variants, indicating their role in defining the patient cohort and confirming the presence of a disease subtype (NSCLC). Oncogenic: The mention of EGFR mutations, including G719C, L858R, and S768I, suggests that these somatic variants contribute to tumor development or progression in the context of non-small cell lung cancer (NSCLC).
Gene→Variant (gene-first): 1956:G719C 1956:L858R 1956:S768I
Genes: 1956
Variants: G719C L858R S768I
Among 550 patients included in cfDNA analysis, median PFS in everolimus vs placebo arms was similar in patients with tumours that had wild-type or mutant PIK3CA (hazard ratio (HR), 0.43 and 0.37, respectively). Everolimu
[Paragraph-level] PMCID: PMC5355930 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the correlation between PIK3CA mutations (H1047R, E545K, E542K) and the response to the therapy everolimus, indicating that these variants are associated with treatment outcomes. Oncogenic: The mention of PIK3CA mutations in the context of tumor analysis suggests that these somatic variants contribute to tumor development or progression, particularly in relation to their response to therapy.
Gene→Variant (gene-first): 5290:E542K 5290:E545K 5290:H1047R
Genes: 5290
Variants: E542K E545K H1047R
PIK3CA H1047R, E545K, and E542K mutations in plasma-derived cfDNA were analysed by droplet digital PCR (ddPCR). Median PFS was estimated for patient subgroups defined by PIK3CA mutations in each treatment arm.
[Paragraph-level] PMCID: PMC5355930 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Diagnostic, Prognostic
Justification: Diagnostic: The passage discusses the analysis of PIK3CA mutations to define patient subgroups, indicating that these variants are used to classify or associate with a disease or subtype. Prognostic: The mention of estimating median progression-free survival (PFS) for patient subgroups defined by PIK3CA mutations suggests a correlation with disease outcome independent of therapy.
Gene→Variant (gene-first): 5290:E542K 5290:E545K 5290:H1047R
Genes: 5290
Variants: E542K E545K H1047R
We next selected two gastroesophageal PDX models with HER2 overexpression (IHC 3+) and ERBB2 amplification. We tested PDX.003.230, a model that is HER2 3+ and ERBB2 amplified. This model was also noted to have an ERBB2 T
[Paragraph-level] PMCID: PMC10618648 Section: RESULTS PassageIndex: 20
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The T733I mutation is associated with resistance to lapatinib and sensitivity to adavosertib, indicating its role in predicting treatment response. Oncogenic: The T733I mutation is described as weakly transforming, suggesting it contributes to tumor development or progression in the context of the PDX model.
Gene→Variant (gene-first): 2064:T733I
Genes: 2064
Variants: T733I
We first assessed the combination of T-DXd with adavosertib in PDXs with low HER2 expression. PDX.003.204 (HER2 2+ IHC, CCNE1 amplified) demonstrated modest tumor growth inhibition with T-DXd monotherapy as shown by a re
[Paragraph-level] PMCID: PMC10618648 Section: RESULTS PassageIndex: 16
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage indicates that ERBB2 mutations (V777L, G778A) were identified in the tyrosine kinase domain, suggesting that these somatic variants contribute to tumor development or progression. Functional: The mention of ERBB2 mutations in the tyrosine kinase domain implies that these variants may alter molecular or biochemical function, which is characteristic of functional evidence.
Gene→Variant (gene-first): 2064:G778A 2064:V777L
Genes: 2064
Variants: G778A V777L
Apoptosis was assessed by annexin V staining to determine the effects of adavosertib in combination with DXd or T-DXd in MKN7 cells. Although both DXd and T-DXd were capable of inducing apoptosis (5-20%), combination of
[Paragraph-level] PMCID: PMC10618648 Section: RESULTS PassageIndex: 11
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 2064:E in 72
Genes: 2064
Variants: E in 72
Across the study cohort of 151 tumors (Figs. 2-4; Supplementary Table 4), KIAA1549-BRAF fusions were detected in PAs, two pilomyxoid astrocytomas (PMAs), and a single brainstem ganglioglioma, and were present in 59%, 90%
[Paragraph-level] PMCID: PMC3727232 Section: RESULTS PassageIndex: 11
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the detection of BRAF:p.V600E mutations in various tumor types, indicating its association with specific tumor classifications, which supports its use as a biomarker for diagnosis. Oncogenic: The H3F3A:p.K27M mutation is described as being present in specific tumor types, indicating its contribution to tumor development or progression.
Gene→Variant (gene-first): 3021:p.K27M 673:p.V600E
Genes: 3021 673
Variants: p.K27M p.V600E
Only four of 39 tumors (10%) in the WGS series lacked a MYB/MYBL1 rearrangement, FGFR1 alteration, or aberration of a gene in the NF1/RAS/RAF pathway. One of these, SJLGG034, was an oligodendroglioma from a patient aged
[Paragraph-level] PMCID: PMC3727232 Section: RESULTS PassageIndex: 6
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 1106:p.D1722V 1029:p.P101L 3417:p.R132H 23152:p.S726R 23152:p.V676fs
Genes: 1106 1029 3417 23152
Variants: p.D1722V p.P101L p.R132H p.S726R p.V676fs
Remarkably, the median number of non-silent somatic sequence mutations and SVs per tumor in the WGS (discovery) series was one, suggesting that few genetic alterations are required for oncogenesis (Fig. 1; Supplementary
[Paragraph-level] PMCID: PMC3727232 Section: RESULTS PassageIndex: 5
Evidence Type(s): Oncogenic, Diagnostic
Justification: Oncogenic: The passage discusses the H3F3A:p.K27M mutation and BRAF:p.V600E mutation as recurrent abnormalities in specific tumor types, indicating their contribution to tumor development or progression. Diagnostic: The mention of BRAF:p.V600E mutations being frequent in pleomorphic xanthoastrocytomas suggests its use in defining or classifying this subtype of tumor.
Gene→Variant (gene-first): 3021:p.K27M 673:p.V600E
Genes: 3021 673
Variants: p.K27M p.V600E
A relational scholarly practice is about developing a relationship withIndigenous intellect. I am going to encourage you, dear reader, to developa rich, deep, and reciprocal relationship to the land you dwell on and theIndigenous people of that land—to carry those histories, cultures, andteachings with you in your writing, research, teaching, and everyday prac-tice.
discussed in class
“To think about rhetoric, we must think about bodies. To do thismeans also to articulate how scholars’ own bodies have intimately informedour disciplinary understanding of rhetoric” (39). To develop a relationa
discussed in class - it is the bodies that partake in/make the culture
We detected somatic mutations in 10 of 16 specimens (63%). Eight had KRAS mutations [G12D (n = 5), G12V (n = 3)] and two had BRAF mutations [V600E (n = 1), Q636X (n = 1)]. We found no difference in age, sex, presenting s
[Paragraph-level] PMCID: PMC6938308 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Oncogenic, Diagnostic
Justification: Oncogenic: The passage discusses somatic mutations in KRAS and BRAF, indicating that these variants contribute to tumor development as they are detected in specimens from patients with AVM. Diagnostic: The presence of specific mutations (G12D, G12V, V600E, Q636X) is used to classify and confirm the mutation status of patients, which is relevant for understanding their disease.
Gene→Variant (gene-first): 3845:G12D 3845:G12V 673:Q636X 673:V600E
Genes: 3845 673
Variants: G12D G12V Q636X V600E
We next examined how these function scores varied in apparently healthy populations (Figures 3C and 3D). The gnomAD database lists 744 of the scored MSH2 missense variants, nearly all rare (742/744 with minor allele freq
[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 13
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the variant p.Ala636Pro scored as deleterious in an assay, indicating that it alters molecular or biochemical function. Oncogenic: The context of the passage suggests that the variant is associated with bi-allelic MMR loss, which contributes to tumor development in pediatric-onset cancer syndromes, indicating its role in oncogenesis.
Gene→Variant (gene-first): 4436:p.Ala636Pro
Genes: 4436
Variants: p.Ala636Pro
Each MSH2 mutant cell pool was then selected en masse for MMR deficiency. To allow comparison across pools, each was spiked with barcoded control cells (KO+WT: 10% of cells; KO+p.Ala636Pro: 0.5%). Pools were then grown u
[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the selection of MSH2 mutant cells, specifically the p.Ala636Pro variant, in the context of MMR deficiency, indicating that this somatic variant contributes to tumor development or progression. Functional: The passage describes the behavior of the p.Ala636Pro variant in a selective environment, suggesting that it alters the molecular function of the MSH2 protein, as evidenced by the enrichment of these cells under selective conditions.
Gene→Variant (gene-first): 4436:p.Ala636Pro
Genes: 4436
Variants: p.Ala636Pro
As a readout for MSH2 function, we leveraged selection with the purine analog 6-thioguanine (6-TG). Incorporation of 6-TG is selectively toxic to MMR-proficient cells, as it creates lesions that the MMR machinery recogni
[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 4
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the p.Ala636Pro variant affects the sensitivity to 6-thioguanine, indicating that it alters the molecular function of MSH2 in the context of mismatch repair. Oncogenic: The passage implies that the p.Ala636Pro variant is pathogenic and contributes to the resistance of cells to 6-thioguanine, suggesting a role in tumor development or progression.
Gene→Variant (gene-first): 4436:p.Ala636Pro
Genes: 4436
Variants: p.Ala636Pro
We established a human cell system to model MSH2 variant function using the near-haploid, mismatch repair proficient cell line HAP1 (Figures 1A and 1C). First, to disrupt MMR, we derived clonal MSH2 knockout cells bearin
[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 3
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the p.Ala636Pro variant affects the expression levels of MSH2 protein, indicating that it alters molecular function by being barely detectable compared to wild-type MSH2, which demonstrates its destabilizing effect. Oncogenic: The passage describes the use of the p.Ala636Pro variant in a model to disrupt mismatch repair (MMR), suggesting that this somatic variant contributes to tumor development or progression by affecting MSH2 function.
Gene→Variant (gene-first): 4436:p.Ala636Pro
Genes: 4436
Variants: p.Ala636Pro
We defined mutations in druggable tyrosine kinase domains including in ERBB2 (a V777L and a 755-759 LRENT in frame deletion homologous to gefitinib-activating EGFR mutations in lung cancer ), as well as in DDR1 (A829V, R
[Paragraph-level] PMCID: PMC3383766 Section: RESULTS PassageIndex: 21
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses mutations in specific genes that are associated with druggable tyrosine kinase domains, indicating their relevance in defining or classifying disease subtypes. Oncogenic: The mention of mutations in tyrosine kinase domains suggests that these variants may contribute to tumor development or progression, particularly in the context of cancer-related mutations.
Gene→Variant (gene-first): 780:A829V 207:C77F 405:D735H 3084:E583D 2048:E924K 5156:M875L 780:R611C 208:S11F 3169:S375F 2064:V777L
Genes: 780 207 405 3084 2048 5156 208 3169 2064
Variants: A829V C77F D735H E583D E924K M875L R611C S11F S375F V777L
To study clinical correlations, mutation recurrence screening was conducted on an additional 240 cases (Supplementary Table 8 and Supplementary Fig. 1). By combining WGS, exome, and recurrence screening data, we determin
[Paragraph-level] PMCID: PMC3383766 Section: RESULTS PassageIndex: 10
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage indicates that the M294K mutation in GATA3 is one of several mutations that include truncation events, suggesting a role in functional inactivation of the protein. Oncogenic: The mention of M294K as a recurrent mutation in tumors suggests that it may contribute to tumor development or progression, particularly in the context of GATA3 being identified as a tumor suppressor.
Gene→Variant (gene-first): 2625:M294K
Genes: 2625
Variants: M294K
We also identified three SMGs (LDLRAP1, AGTR2, and STMN2), not previously implicated in cancer. A missense and a nonsense mutation were observed in LDLRAP1, a gene associated with familial hypercholesterolemia. AGTR2, an
[Paragraph-level] PMCID: PMC3383766 Section: RESULTS PassageIndex: 8
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage mentions that AGTR2 harbored two missense mutations (V184I and R251H) and describes AGTR2 as a gene associated with familial hypercholesterolemia, indicating its role in defining or classifying a disease. Oncogenic: The passage discusses mutations in AGTR2 and their potential involvement in angiotensin signaling and tissue fibrosis, which are relevant to tumor development or progression, suggesting a role in oncogenesis.
Gene→Variant (gene-first): 186:R251H 186:V184I
Genes: 186
Variants: R251H V184I
Thirteen mutations (3 nonsense, 6 frame-shift indels, 2 in-frame deletions and 2 missense) were identified in MAP3K1 (Table 1 and Fig. 2), a serine/threonine kinase that activates the ERK and JNK kinase pathways through
[Paragraph-level] PMCID: PMC3383766 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses mutations in RUNX1, which is implicated in the M2 subtype of AML, indicating that these somatic variants contribute to tumor development or progression. Functional: The passage mentions that mutations in RUNX1 affect its role as a transcription factor, which suggests that these variants alter molecular or biochemical function.
Gene→Variant (gene-first): 9757:G168E 23451:K666Q 23451:K700E 4216:N104S 861:R166Q 1588:R169K 51742:S184L
Genes: 9757 23451 4216 861 1588 51742
Variants: G168E K666Q K700E N104S R166Q R169K S184L
Candidate canonical RBDs mainly include the RNA recognition motif (RRM), zinc fingers (ZF), tryptophan-aspartic acid 40 (WD40), K homology (KH) domain, double-stranded RNA-binding motif (DSRM), TUDOR domain, cold shock d
[Paragraph-level] PMCID: PMC7226056 Section: RESULTS PassageIndex: 7
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 7015:tryptophan-aspartic acid 40
Genes: 7015
Variants: tryptophan-aspartic acid 40
Next, we analyzed the expression patterns of RBPs in different types of glioma patients and compared their abundance in expression levels. In our studies, a global analysis of the expression of the mRNA levels of RBPs re
[Paragraph-level] PMCID: PMC7226056 Section: RESULTS PassageIndex: 5
Evidence Type(s): Diagnostic, Oncogenic, Prognostic
Justification: Diagnostic: The passage discusses the reclassification of glioma patients into different types based on expression levels and molecular alterations, indicating that these variants are used to define or classify the disease. Oncogenic: The mention of TERT mutation in gliomas suggests that this somatic variant may contribute to tumor development or progression, as it is associated with different expression levels in tumor types. Prognostic: The passage notes that molecular alterations in gliomas are linked to clinical phenotypes and can predict outcomes, such as overall survival, indicating a prognostic relationship.
Gene→Variant (gene-first): 7015:CGGA 94) in the TCGA
Genes: 7015
Variants: CGGA 94) in the TCGA
In the M6620-carboplatin combination cohort, a confirmed RECISTv1.1 PR was observed in a 54-year-old woman with heavily pretreated metastatic high-grade serous ovarian cancer, who was treated at the combination RP2D. Bio
[Paragraph-level] PMCID: PMC7499606 Section: RESULTS PassageIndex: 18
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The TP53 Y220C missense mutation is described as a "deleterious somatic mutation," indicating its contribution to tumor development or progression. Predictive: The passage discusses the patient's response to various therapies, including PARP inhibitors and the M6620-carboplatin combination therapy, suggesting that the Y220C variant may correlate with treatment response.
Gene→Variant (gene-first): 7157:Y220C
Genes: 7157
Variants: Y220C
Among the 87 patients of the study population, BRAF was mutated in 13 cases (15%). KRAS codons 61, 146 and BRAF V600E mutations were mutually exclusive. None of the patients bearing BRAF mutation responded to the treatme
[Paragraph-level] PMCID: PMC2736831 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Prognostic, Oncogenic
Justification: Predictive: The passage indicates that none of the patients with the BRAF V600E mutation responded to the treatment, suggesting a correlation between the variant and resistance to therapy. Prognostic: The passage reports that BRAF mutation is associated with significantly shorter overall survival (OS) and a trend towards shorter progression-free survival (PFS), indicating its impact on disease outcome independent of therapy. Oncogenic: The BRAF V600E mutation is described as a somatic variant that is part of the study population's tumor mutations, contributing to tumor development or progression.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
NTRK-fused gliomas in our cohort demonstrated concurrent aberrations involving CDKN2A/2B, TERT promoter, TP53, PTEN, EGFR, ATRX, RB1, IDH1, polysomy 7, ROS1, PIK3CA, NF1, and MDM4. The frequency of these genetic aberrati
[Paragraph-level] PMCID: PMC7362646 Section: RESULTS PassageIndex: 11
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses the IDH1 p.R132H mutation as part of the genetic aberrations detected in gliomas, indicating its contribution to tumor development or progression in the context of high-grade gliomas.
Gene→Variant (gene-first): 3417:p.R132H
Genes: 3417
Variants: p.R132H
Although first-line crizotinib treatment leads to clinical benefit in ROS1+ lung cancer, high prevalence of crizotinib-resistant ROS1-G2032R mutation and progression in the central nervous system (CNS) represents a thera
[Paragraph-level] PMCID: PMC10283448 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the high prevalence of the crizotinib-resistant ROS1-G2032R mutation and its implications for treatment response, indicating a correlation with resistance to therapy. Oncogenic: The mention of the ROS1-G2032R mutation in the context of crizotinib resistance suggests that it contributes to tumor progression, which aligns with the definition of an oncogenic variant.
Gene→Variant (gene-first): 6098:G2032R
Genes: 6098
Variants: G2032R
Targeted sequencing results show a common driver mutation KRAS p.G12V (8.72%) along with two splicing mutations of DDR gene PALB2 in her resected primary lesion (online supplementary table S1). No alterations of other ma
[Paragraph-level] PMCID: PMC7342819 Section: RESULTS PassageIndex: 2
Evidence Type(s): Diagnostic, Predisposing, Oncogenic
Justification: Diagnostic: The passage discusses the identification of the KRAS p.G12V mutation and the PALB2 mutations in the context of a primary lesion, indicating their association with the disease. Predisposing: The PALB2 c.3114-1G>A mutation is explicitly described as a germline mutation detected in peripheral blood cells, suggesting it confers inherited risk for developing disease. Oncogenic: The PALB2 c.2514+1G>C mutation is described as a somatic mutation, which is associated with tumor development in the context of the primary lesion.
Gene→Variant (gene-first): 79728:c.2514+1G>C 79728:c.3114-1G>A 3845:p.G12V
Genes: 79728 3845
Variants: c.2514+1G>C c.3114-1G>A p.G12V
To further explore potential functions of these SNPs, we performed the eQTL analysis for selected SNPs and mRNA expression of their corresponding genes in cancer tissues by using TCGA dataset. As shown in Figure 3, the a
[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 13
Evidence Type(s): Functional, Prognostic
Justification: Functional: The passage discusses how the alleles of rs16879870 and rs854936 are associated with increased mRNA expression levels of their corresponding genes, indicating an alteration in molecular function. Prognostic: The passage reports that higher expression levels of the genes GJB7 and RTN4R correlate with worse prognosis in HNSCC patients, indicating a relationship with disease outcome independent of therapy.
Gene→Variant (gene-first): NA:rs16879870 NA:rs854936
Genes: NA
Variants: rs16879870 rs854936
Furthermore, stratification analyses were conducted to examine whether the effects of risk genotypes on death with HNSCC was modified by sex, age, smoking, drinking status, and clinical stage. However, the heterogeneity
[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 11
Evidence Type(s): Prognostic
Justification: Prognostic: The passage discusses the effects of risk genotypes, including rs2761591, on death with HNSCC, indicating a correlation with disease outcome.
Gene→Variant (gene-first): 341019:rs2761591
Genes: 341019
Variants: rs2761591
ROC model was built to assess the ability of NRG in prediction of HNSCC survival by using the area under the curve (AUC). We constructed two models to compare their ability, one for clinical variables and the other for b
[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 9
Evidence Type(s): Prognostic, Predictive
Justification: Prognostic: The passage discusses the ability of a model to predict survival in HNSCC, indicating a correlation between the variant and disease outcome. Predictive: The mention of using NRG in a prediction model for HNSCC survival suggests a relationship with treatment response or sensitivity, aligning with predictive evidence.
Gene→Variant (gene-first): 2264:AUC from 0
Genes: 2264
Variants: AUC from 0
To provide a better estimation of the hazards of survival, the risk genotypes (i.e., rs16879870 CA+AA, rs2641256 AA, rs2761591 GA, and rs854936 AC) were combined into one variable as the number of risk genotypes (NRG), w
[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 7
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage discusses how the number of risk genotypes (NRG) correlates with the hazard of death in patients with HNSCC, indicating a relationship between the variants and disease outcome. Diagnostic: The variants are used to define and classify patients into groups based on the number of risk genotypes, which is associated with survival outcomes in HNSCC.
Gene→Variant (gene-first): NA:rs16879870 388325:rs2641256 341019:rs2761591 NA:rs854936
Genes: NA 388325 341019
Variants: rs16879870 rs2641256 rs2761591 rs854936
In the discovery stage, univariate and multivariable Cox regression analysis were further performed to evaluate the effects on risk of death for each of selected SNPs (Table 2), with adjusting of age, gender, smoking, dr
[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 6
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage discusses the association of specific SNP genotypes with survival outcomes in HNSCC, indicating that these variants correlate with risk of death independent of therapy. Diagnostic: The passage mentions the classification performance of risk genotypes of selected SNPs, suggesting their use in defining or classifying disease risk.
Gene→Variant (gene-first): NA:rs16879870 388325:rs2641256 341019:rs2761591 NA:rs854936
Genes: NA 388325 341019
Variants: rs16879870 rs2641256 rs2761591 rs854936
As shown in Supplementary Figure 1, after QC, we performed Cox proportional hazards regression models to assess associations of 31,075 qualified genetic variants with HNSCC survival, with adjustment for age, gender, smok
[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 5
Evidence Type(s): Prognostic
Justification: Prognostic: The passage discusses the correlation of specific SNPs with HNSCC patients' survival, indicating that these variants are associated with disease outcome independent of therapy.
Gene→Variant (gene-first): NA:rs16879870 388325:rs2641256 341019:rs2761591 NA:rs854936
Genes: NA 388325 341019
Variants: rs16879870 rs2641256 rs2761591 rs854936
We recently reported the results of a glioblastoma clinical trial with EGFR kinase inhibitors which associated clinical responses to the coexpression of EGFRvIII and PTEN. To investigate whether clinical responses might
[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 17
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the association of the R108K variant with clinical responses to EGFR kinase inhibitors, indicating a correlation with treatment response. Oncogenic: The R108K variant is identified in gliomas, suggesting its potential role in tumor development or progression, particularly in the context of EGFR amplification.
Gene→Variant (gene-first): 1956:R108K
Genes: 1956
Variants: R108K
The presence of identical missense mutations in multiple patient samples and their oncogenicity in standard transformation assays suggest that these mutants play a role in gliomagenesis. It also raises the question wheth
[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 16
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how the presence of EGFR missense mutants, including L858R and L861Q, may sensitize transformed cells to EGFR kinase inhibitors, indicating a correlation with treatment response. Oncogenic: The identical missense mutations are described as having oncogenicity and playing a role in gliomagenesis, suggesting that these somatic variants contribute to tumor development.
Gene→Variant (gene-first): 1956:L858R 1956:L861Q 1956:T790M
Genes: 1956
Variants: L858R L861Q T790M
We also expressed selected EGFR mutants (R108K, T263P, A289V, G598V, L861Q) in murine hematopoietic cells (Ba/F3 cells) which do not express any EGFR family members but otherwise retain functional properties of the EGF-s
[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 14
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the EGFR mutants (R108K, T263P, A289V, G598V, L861Q) alter the molecular function of the EGF-signaling pathway, specifically showing increased tyrosine phosphorylation and differences in receptor downregulation in response to EGF stimulation.
Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:R108K 1956:T263P
Genes: 1956
Variants: A289V G598V L861Q R108K T263P
Signal transduction through EGFR is determined by its basal catalytic activity, receptor activation by ligand, and signal termination through intracellular compartmentalization of the receptor-ligand complex, receptor de
[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 13
Evidence Type(s): Functional
Justification: Functional: The examination of other EGFR missense mutants (T263P, G598V, L861Q) also shows an increase in phosphotyrosine content, suggesting that these variants similarly affect the molecular function of the receptor.
Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:T263P
Genes: 1956
Variants: A289V G598V L861Q T263P
To further analyze the oncogenic potential of the EGFR mutants, NIH-3T3 subclones stably expressing the same missense mutant receptors (encoding R108K, T263P, A289V, G598V, and L861Q) were inoculated subcutaneously into
[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 11
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage describes how NIH-3T3 cells expressing the EGFR missense mutants (R108K, T263P, A289V, G598V, and L861Q) produced large tumors in mice, indicating that these variants contribute to tumor development.
Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:R108K 1956:T263P
Genes: 1956
Variants: A289V G598V L861Q R108K T263P
To test the oncogenicity of the glioma-related EGFR missense mutations, we transduced NIH-3T3 fibroblasts with retroviruses encoding either wild-type EGFR or selected EGFR missense mutants (encoding R108K, T263P, A289V,
[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 10
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses the oncogenicity of EGFR missense mutations, indicating that the expression of these variants (R108K, T263P, A289V, G598V, and L861Q) in NIH-3T3 cells leads to anchorage-independent colony formation, a hallmark of tumorigenic behavior.
Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:R108K 1956:T263P
Genes: 1956
Variants: A289V G598V L861Q R108K T263P
To define which fraction of the EGFR pool represented the mutant allele in gliomas with EGFR missense mutations, we employed a PCR-cloning strategy previously used by our laboratories for mutation detection in clinical s
[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 5
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the prevalence of specific EGFR missense mutations (R108K, T263P, A289V, and G598V) in gliomas, indicating their association with the disease and their representation in the receptor pool, which supports their use in defining or classifying the disease. Oncogenic: The mention of EGFR missense mutations in the context of gliomas suggests that these somatic variants contribute to tumor development or progression, as they are associated with the receptor pool in tumor samples.
Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:R108K 1956:T263P
Genes: 1956
Variants: A289V G598V R108K T263P
In all, we identified EGFR missense mutations in 14.4% (19/132) of glioblastomas, 12.5% (1/8) of glioblastoma cell lines, and none (0/11) in lower-grade gliomas. Only one tumor sample harbored a missense mutation in the
[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 4
Evidence Type(s): Diagnostic, Oncogenic, Predisposing
Justification: Diagnostic: The passage discusses the identification of EGFR missense mutations in glioblastomas and their association with the disease, indicating that these mutations can be used to classify or define the tumor type. Oncogenic: The passage mentions that the identified EGFR mutations contribute to tumor development in glioblastomas, particularly noting the presence of somatic mutations in the tumor samples. Predisposing: The passage specifies that one of the mutations (E330K) was identified as germline, indicating it confers inherited risk for developing disease.
Gene→Variant (gene-first): 1956:A289 1956:A289D 1956:A289T 1956:E330K 1956:L861Q 1956:R108 1956:R324L
Genes: 1956
Variants: A289 A289D A289T E330K L861Q R108 R324L
Four human NSCLC cell lines were employed, expressing either of the following forms of the EGFR: (i) the wild-type receptor (QG56 cells), (ii) a mutant with an exon 19 in-frame deletion (HCC827 cells), (iii) a mutant wit
[Paragraph-level] PMCID: PMC4385014 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the sensitivity of NSCLC cell lines with specific EGFR mutations (L858R and T790M) to the anti-proliferative effect of erlotinib, indicating a correlation with treatment response. Oncogenic: The presence of the L858R and T790M mutations in the cell lines suggests that these somatic variants contribute to tumor development or progression, as they are associated with specific cancer cell lines.
Gene→Variant (gene-first): 1956:L858R 1956:T790M
Genes: 1956
Variants: L858R T790M
Four patients harbored hotspot PIK3CA mutations most commonly seen in cancer. Two of these patients had a mosaic p.Glu542Lys mutation. Patient LR12-183 had a novel constellation of features including megalencephaly with
[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 19
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the presence of specific PIK3CA mutations in patients with distinct clinical features, indicating that these mutations are associated with certain syndromes, such as linear nevus sebaceous or Schimmelpenning syndrome and CLOVES syndrome. Oncogenic: The passage mentions that the PIK3CA mutations are "hotspot" mutations commonly seen in cancer, suggesting that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 5290:p.Glu542Lys 5290:p.Glu545Lys 5290:p.His1047Arg
Genes: 5290
Variants: p.Glu542Lys p.Glu545Lys p.His1047Arg