The role of E152 in venetoclax affinity
[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive
Justification: Predictive: The passage discusses the role of E152 in venetoclax affinity, indicating a correlation with response or sensitivity to the therapy.
Gene→Variant (gene-first): 596:E152
Genes: 596
Variants: E152
SPR experiments were performed using a BIMBH3 or BAXBH3 immobilised sensor surface with BCL-2 mutants as the analyte and determining venetoclax affinity by competition experiments, (Fig. 3, Table 2 and Supplementary Fig.
[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 8
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses how the BCL-2 mutants, including G101V, F104L, and F104C, exhibit varying affinities for venetoclax, indicating their role in providing resistance to therapy. Functional: The passage describes how the BCL-2 mutants maintain tight binding to BH3 domains, which alters their molecular function and contributes to their ability to prevent apoptosis.
Gene→Variant (gene-first): 596:F104C 596:F104L 596:G101V
Genes: 596
Variants: F104C F104L G101V
To understand how these BCL-2 mutations compromise drug binding we solved crystal structures of both complexes (Table 1 and Fig. 2). The G101V mutation resides on the BCL-2 alpha2 helix packing against the alpha5 helix a
[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 5
Evidence Type(s): Functional, Predictive
Justification: Functional: The passage discusses how the G101V mutation alters drug binding by changing the molecular interactions within the BCL-2 structure, indicating an alteration in biochemical function. Predictive: The evidence suggests that the G101V mutation impacts the binding affinity of venetoclax, which correlates with the response to this specific therapy.
Gene→Variant (gene-first): 596:E152 596:G101 596:G101A 596:G101V
Genes: 596
Variants: E152 G101 G101A G101V
The BCL-2 mutation G101V reduces venetoclax affinity and confers drug resistance in patients with chronic lymphocytic leukaemia. Here, the authors present crystal structures and biochemical analyses of venetoclax bound t
[Paragraph-level] PMCID: PMC6547681 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Functional
Justification: Predictive: The variant G101V is associated with drug resistance to venetoclax in patients, indicating a correlation with treatment response. Functional: The passage discusses the biochemical analyses of the G101V mutant, revealing how it alters the affinity of venetoclax, which relates to its molecular function.
Gene→Variant (gene-first): 596:G101V
Genes: 596
Variants: G101V
Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has reveale
[Paragraph-level] PMCID: PMC6547681 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the emergence of the G101V mutation in patients failing therapy with venetoclax, indicating a correlation between the variant and resistance to this specific therapy. Functional: The passage describes how the G101V mutation alters the binding of venetoclax to BCL-2, indicating a change in molecular function related to drug resistance.
Gene→Variant (gene-first): 596:E152 596:E152A 596:G101V 596:V101
Genes: 596
Variants: E152 E152A G101V V101
'Classical' mutations in the EGFR tyrosine kinase domain (exons 18, 19 and 21) have been associated with sensitivity to tyrosine kinase inhibitors (TKIs) in patients with NSCLC. The aim of the current study was to evalua
[Paragraph-level] PMCID: PMC2360265 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the association of classical mutations, including G719X and L858R, with sensitivity to tyrosine kinase inhibitors (TKIs) in patients with NSCLC, indicating a correlation with treatment response. Diagnostic: The mention of classical mutations in the EGFR tyrosine kinase domain being associated with sensitivity to TKIs suggests that these variants can be used to classify or define a subtype of disease in NSCLC patients.
Gene→Variant (gene-first): 1956:G719X 1956:L858R
Genes: 1956
Variants: G719X L858R
The DCR was significantly higher in patients of the 'classical' mutations than in patients of the 'wild-type' (90.9 and 43.3%, respectively; P=0.006) group; conversely, there was no significant difference between the DCR
[Paragraph-level] PMCID: PMC2360265 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the disease control rate (DCR) in relation to specific mutations, indicating a correlation between the presence of mutations (including L858R, G719D, and E746V) and treatment outcomes, which suggests predictive evidence regarding therapy response. Diagnostic: The mention of 'classical' mutations and their association with disease control rates implies that these mutations, including L858R, G719D, and E746V, are used to classify or define a subtype of the disease.
Gene→Variant (gene-first): 1956:E746V 1956:G719D 1956:L858R
Genes: 1956
Variants: E746V G719D L858R
In 2017, the third-generation EGFR inhibitor osimertinib was approved for use in patients who developed the EGFR T790M mutation as a mechanism of resistance. In this year, of the 254 patients who received an EGFR inhibit
[Paragraph-level] PMCID: PMC8307492 Section: RESULTS PassageIndex: 18
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the T790M mutation as a mechanism of resistance to the EGFR inhibitor osimertinib, indicating its correlation with treatment response. Oncogenic: The T790M mutation is described as contributing to resistance in patients treated with EGFR inhibitors, suggesting its role in tumor progression.
Gene→Variant (gene-first): 1956:G719S 1956:L858R 1956:L861Q 1956:T790M
Genes: 1956
Variants: G719S L858R L861Q T790M
The proportion of patients receiving first-line targeted therapy was highest for those with an exon 19 deletion (321/390; 82%) or L858R mutation (227/287; 79%), lower for those with uncommon, actionable variants (69/103;
[Paragraph-level] PMCID: PMC8307492 Section: RESULTS PassageIndex: 16
Evidence Type(s): Predictive, Prognostic
Justification: Predictive: The passage discusses the proportion of patients receiving first-line targeted therapy based on the presence of the L858R mutation, indicating a correlation with treatment response. Prognostic: The median overall survival (OS) for patients with the L858R mutation is reported, demonstrating its correlation with disease outcome independent of therapy.
Gene→Variant (gene-first): 1956:L858R
Genes: 1956
Variants: L858R
EGFR mutation analysis in non-small-cell lung cancer (NSCLC) patients is currently standard-of-care. We determined the uptake of EGFR testing, test results and survival of EGFR-mutant NSCLC patients in the Netherlands, w
[Paragraph-level] PMCID: PMC8307492 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the association of the L858R variant with overall survival (OS) in patients treated with first-line EGFR inhibitors, indicating its relevance to treatment response. Oncogenic: The L858R variant is mentioned in the context of EGFR mutations in non-small-cell lung cancer (NSCLC), suggesting its role in tumor development or progression as part of the broader analysis of clinically actionable EGFR mutations.
Gene→Variant (gene-first): 1956:L858R
Genes: 1956
Variants: L858R
Oncogenic mutations in the serine/threonine kinase B-RAF are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAFV600E mutation predicts a dependency on the mitogen activated prot
[Paragraph-level] PMCID: PMC3058384 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The B-RAFV600E mutation predicts a dependency on the MAPK signaling cascade in melanoma, and this is validated by the success of RAF and MEK inhibitors in clinical trials, indicating a correlation with treatment response. Oncogenic: The passage discusses oncogenic mutations in B-RAF, specifically the B-RAFV600E mutation, which is implicated in tumor development and progression in malignant melanomas.
Gene→Variant (gene-first): 673:B-RAFV600E 673:serine/threonine
Genes: 673
Variants: B-RAFV600E serine/threonine
In parallel, a recent study evaluated the influence of 36 RAD51C missense variants on HR activity of U2OS and 21 on HR activity of MCF10A cells. Importantly, 18 of 36 evaluated in U2OS and 13 of 21 evaluated in MCF10A ce
[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 10
Evidence Type(s): Functional, Predictive
Justification: Functional: The passage discusses how the L138F variant alters HDR activity in different cell lines, indicating a change in molecular function. Predictive: The passage mentions the sensitivity of variants, including L138F, to cisplatin and olaparib, suggesting a correlation with response to these therapies.
Gene→Variant (gene-first): 5889:L138F
Genes: 5889
Variants: L138F
To confirm the functional effects of RAD51C variants in a human cell line, RAD51C WT and 7 deleterious or intermediate missense variants in the HDR assay (G130R, K131I, T132R, Q133E, L138F, R168G and G302V) were introduc
[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the sensitivity of specific RAD51C variants (G130R, K131I, T132R, Q133E, and G302V) to olaparib, indicating a correlation with response to therapy. Functional: The passage describes the introduction of RAD51C variants into a cell line and assesses their effects on homologous recombination repair (HDR), indicating that these variants alter molecular function.
Gene→Variant (gene-first): 5889:G130R 5889:G302V 5889:K131I 5889:L138F 5889:Q133E 5889:R168G 5889:T132R
Genes: 5889
Variants: G130R G302V K131I L138F Q133E R168G T132R
An inability to form RAD51 foci at the sites of DNA DSBs is a key component of an HR deficient phenotype. Because disruption of RAD51C substantially decreases RAD51 foci formation the influence of RAD51C missense variant
[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 7
Evidence Type(s): Functional, Predictive
Justification: Functional: The passage discusses how RAD51C missense variants alter RAD51 foci formation in response to DNA damage, indicating a change in molecular function related to DNA repair mechanisms. Predictive: The mention of "drug response findings" suggests that the variants may correlate with sensitivity or resistance to a specific therapy, indicating predictive evidence.
Gene→Variant (gene-first): 5889:A155E 5889:C135Y 5889:C147Y 5888:D108G 5889:D109Y 5889:D159Y 5889:G306R 5889:P21S 5889:V140E 5889:p.Ala155Glu 5888:p.Asp108Gly 5889:p.Asp109Tyr 5889:p.Asp159Tyr 5889:p.Cys147Tyr 5889:p.Gly306Arg 5889:p.Pro21Ser 5889:p.Val140Glu
Genes: 5889 5888
Variants: A155E C135Y C147Y D108G D109Y D159Y G306R P21S V140E p.Ala155Glu p.Asp108Gly p.Asp109Tyr p.Asp159Tyr p.Cys147Tyr p.Gly306Arg p.Pro21Ser p.Val140Glu
RAD51C loss promotes HR deficiency and sensitizes cells to cisplatin and olaparib PARP inhibitor. Thus, the influence of 60 RAD51C missense variants from the HDR assay (30 deleterious, 23 neutral, and 7 intermediate) on
[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 5
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the influence of RAD51C missense variants on the response to cisplatin and olaparib, indicating a correlation between the variants and treatment sensitivity. Functional: The passage describes how the variants affect IC50 values in the HDR assay, suggesting that they alter molecular function related to drug response.
Gene→Variant (gene-first): 5889:E94K 5889:G306R 5889:p.Glu94Lys 5889:p.Gly306Arg
Genes: 5889
Variants: E94K G306R p.Glu94Lys p.Gly306Arg
Firstly, the level of total STAT3 in two HCC patient samples appeared to be higher than that in corresponding adjacent normal tissues. Interestingly, treatment of ruxolitinib led to a significant reduction (50%) of the p
[Paragraph-level] PMCID: PMC4868698 Section: RESULTS PassageIndex: 14
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the treatment of ruxolitinib and its effects on the phosphorylation level of STAT3 in tumors with the JAK1 S703I mutation, indicating a correlation with treatment response. Oncogenic: The mention of the JAK1 S703I mutation in the context of tumor models suggests that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 3716:S703I
Genes: 3716
Variants: S703I
In vivo efficacy studies of JAK1/2 inhibitor, ruxolitinib, were conducted in these four JAK1-mutant models and a JAK1-WT PDX model as a control (Figure 3A). The results showed that, only in LI-03-0191 model bearing JAK1S
[Paragraph-level] PMCID: PMC4868698 Section: RESULTS PassageIndex: 11
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the sensitivity of the JAK1S703I mutation to the JAK1/2 inhibitor ruxolitinib, indicating a correlation with treatment response. Oncogenic: The passage suggests that the JAK1S703I mutation may play a critical role in tumorigenesis, indicating its contribution to tumor development.
Gene→Variant (gene-first): 3716:S703I
Genes: 3716
Variants: S703I
Anti-tumor activity of ruxolitinib in JAK1S703I-mutant PDX model
[Paragraph-level] PMCID: PMC4868698 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the anti-tumor activity of ruxolitinib in a model with the JAK1 S703I mutation, indicating a correlation with response to therapy. Oncogenic: The mention of the JAK1 S703I mutation in the context of a PDX model suggests that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 3716:S703I
Genes: 3716
Variants: S703I
To examine if upregulation of NRG1 is induced by hormone therapy, we treated freshly isolated primary CAFs from CWR22Pc tumors or pCAFs with CSS or Enz. CSS and Enz both induced NRG1 mRNA and protein expression after 7 d
[Paragraph-level] PMCID: PMC7472556 Section: RESULTS PassageIndex: 23
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how NRG1 levels increase after androgen deprivation therapy (ADT) and suggests that these elevated levels are sufficient to promote resistance to ADT, indicating a correlation with treatment response. Oncogenic: The mention of NRG1 promoting resistance to ADT implies a role in tumor development or progression, which aligns with the definition of an oncogenic variant.
Gene→Variant (gene-first): 8850:S7C
Genes: 8850
Variants: S7C
To gain insight into the potential clinical relevance of these findings, we examined NRG1 expression in a cohort of 43 patients with localized prostate cancer who underwent radical prostatectomy surgery, 23 of whom recei
[Paragraph-level] PMCID: PMC7472556 Section: RESULTS PassageIndex: 21
Evidence Type(s): Diagnostic, Predictive
Justification: Diagnostic: The passage discusses the detection of NRG1 expression in patients with localized prostate cancer, indicating its potential role in classifying or defining the disease based on the presence or absence of NRG1 staining. Predictive: The analysis includes a comparison of NRG1 expression in patients who received neoadjuvant ADT versus those who were hormonally intact, suggesting a correlation with treatment response.
Gene→Variant (gene-first): 3084:S6 8850:S7
Genes: 3084 8850
Variants: S6 S7
To carry out the purification, serum-free 22Pc-CAFCM was collected, concentrated, and applied to a Q-Superose anion exchange column, from which we eluted two protein peaks by using 30% and 100% high-salt buffer B (termed
[Paragraph-level] PMCID: PMC7472556 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses resistance-promoting activity and its correlation with HER3 phosphorylation, indicating a relationship with response or resistance to therapy. Functional: The passage describes how the variant affects HER3 phosphorylation activity, suggesting an alteration in molecular function related to resistance-promoting activity.
Gene→Variant (gene-first): 5979:Q8
Genes: 5979
Variants: Q8
Frequent genetic alterations discovered in FGFRs and evidence implicating some as drivers in diverse tumors has been accompanied by rapid progress in targeting FGFRs for anticancer treatments. Wider assessment of the imp
[Paragraph-level] PMCID: PMC5029699 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the impact of FGFR3 kinase domain variants on drug responses and highlights the distinct changes in efficacy of inhibitors based on specific activating mutations, indicating a correlation with treatment response. Oncogenic: The mention of FGFR3 variants as drivers in diverse tumors suggests that these somatic mutations contribute to tumor development or progression.
Gene→Variant (gene-first): 2261:K650E 2261:N540K 2261:R669G
Genes: 2261
Variants: K650E N540K R669G
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
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
In the cBioPortal database, variants of the MAP2K1 gene are reported at frequencies of 1.7% in CRC patients (Table 1) and correlated with worse disease/progression-free survival (Logrank Test P-Value: 1.815e-3), but not
[Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 20
Evidence Type(s): Diagnostic, Prognostic, Predictive, Oncogenic
Justification: Diagnostic: The passage discusses the frequencies of MAP2K1 variants in CRC patients and their association with specific tumor characteristics, indicating their role in defining or classifying the disease. Prognostic: The variants are correlated with worse disease/progression-free survival, suggesting they have prognostic implications independent of therapy. Predictive: The passage mentions that MAP2K1 mutations are associated with de novo and acquired resistance to anti-EGFR MoAbs, indicating a predictive relationship with therapy response. Oncogenic: The variants are described as contributing to a gain of function of the MEK1 protein, which is indicative of their role in tumor development or progression.
Gene→Variant (gene-first): 5604:c.169A>G 5604:c.199G>A 5604:p.Asp67Asn 5604:p.Lys57Glu
Genes: 5604
Variants: c.169A>G c.199G>A p.Asp67Asn p.Lys57Glu
The CNVs were much more frequent among patients with longer PFS. Within this cohort, patient P16 had a significant copy number gain of ERBB2 (78.99) that was confirmed by FISH analysis (data not shown). Patient P16 had a
[Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 16
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the response of patients to cetuximab-based first-line therapy, specifically noting that patient P4, who carries the FBXW7 variant c.1268G>T; p.Gly423Val, had a complete response to this therapy. Diagnostic: The mention of the FBXW7 variant in the context of patient P4's treatment response suggests that it may be used to classify or define the patient's disease or treatment outcome.
Gene→Variant (gene-first): 55294:c.1268G>T 55294:p.Gly423Val
Genes: 55294
Variants: c.1268G>T p.Gly423Val
Finally, we investigated genetic mutation status in biopsies of two patients who progressed on repotrectinib in clinical trial using targeted sequencing. Patient A, a 46-year-old male with a 20 pack-year smoking history,
[Paragraph-level] PMCID: PMC10283448 Section: RESULTS PassageIndex: 14
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses mutations identified in patients who progressed on repotrectinib treatment, suggesting a potential role of these variants in acquired resistance to the therapy. Functional: The passage indicates that further studies are necessary to investigate the functional role of the mutations, implying that these variants may alter molecular or biochemical functions related to resistance mechanisms.
Gene→Variant (gene-first): 1050:196_197insHP 7157:E171G 896:E253Q 2064:H178Q 7157:H179Y 5925:H555R 2064:R143Q
Genes: 1050 7157 896 2064 5925
Variants: 196_197insHP E171G E253Q H178Q H179Y H555R R143Q
The clinical activity of repotrectinib against ROS1 SFM was seen in a 49-year-old female ROS1-rearranged patient who progressed after 44 months of crizotinib treatment with an identified CD74-ROS1 G2032R mutation. The pa
[Paragraph-level] PMCID: PMC10283448 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the clinical activity of repotrectinib in a patient with the G2032R mutation, indicating a response to therapy, which aligns with predictive evidence. Diagnostic: The G2032R mutation is identified in the context of a ROS1-rearranged patient, suggesting its role in defining the patient's disease subtype.
Gene→Variant (gene-first): 6098:G2032R
Genes: 6098
Variants: G2032R
We identified the ROS1-G2032R mutation in YU1079, which was serially established in the same patient as YU1078 but after progressing on crizotinib treatment. Based on recent studies examining lorlatinib and cabozantinib
[Paragraph-level] PMCID: PMC10283448 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of the ROS1-G2032R mutation to various therapies, specifically mentioning the effectiveness of cabozantinib and repotrectinib in inhibiting growth, which correlates with treatment response. Oncogenic: The ROS1-G2032R mutation is implicated in tumor growth, as indicated by the investigation of its effects in Ba/F3 cells and the context of progression on crizotinib treatment, suggesting its role in tumor development.
Gene→Variant (gene-first): 6098:G2032R
Genes: 6098
Variants: G2032R
Repotrectinib overcomes crizotinib-resistant ROS1 G2032R
[Paragraph-level] PMCID: PMC10283448 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive
Justification: Predictive: The passage indicates that repotrectinib is effective against crizotinib-resistant ROS1 G2032R, suggesting a correlation between the variant and response to therapy.
Gene→Variant (gene-first): 6098:G2032R
Genes: 6098
Variants: G2032R
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
We report two inflammatory myofibroblastic tumor (IMT) patients with ALK fusions (RRBP-ALK and TNS1-ALK, respectively). They both received tumor resection surgery and treatment with ALK inhibitors crizotinib followed by
[Paragraph-level] PMCID: PMC7568619 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The variant L1196Q is associated with the development of resistance to ALK inhibitors, and its identification guided the prescription of a newer ALK inhibitor, ceritinib, which resulted in a partial response in the patient. Oncogenic: The passage indicates that the L1196Q mutation is a secondary mutation that developed in the context of drug resistance, suggesting it contributes to tumor progression and the development of resistance to therapy.
Gene→Variant (gene-first): 238:L1196Q
Genes: 238
Variants: L1196Q
P05 was a female patient with EGFR exon 19 deletion-mutant stage IV LUAD with bone metastasis, and ERBB2DeltaEx16 was identified from her plasma sample after progression on osimertinib plus crizotinib ( Table 2 ; Figure
[Paragraph-level] PMCID: PMC9859631 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses various mutations, including Y1230H, D1288N L1195I, and L1195V, which are described as secondary mutations associated with MET TKI resistance, indicating a correlation with treatment response. Oncogenic: The mention of mutations contributing to resistance against targeted therapies suggests that these variants may play a role in tumor development or progression, particularly in the context of lung cancer.
Gene→Variant (gene-first): 79811:D1288N L1195I 79811:L1195V 79811:Y1230H 2064:c.1899-936_1946+520del
Genes: 79811 2064
Variants: D1288N L1195I L1195V Y1230H c.1899-936_1946+520del
P03 was a female patient with EGFR L858R-mutant advanced LUAD with bone metastasis. ERBB2DeltaEx16 was detected after disease progression with osimertinib using her plasma samples but not in the paired tissue rebiopsy (
[Paragraph-level] PMCID: PMC9859631 Section: RESULTS PassageIndex: 11
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the presence of the EGFR L858R variant in a patient with advanced LUAD and its association with resistance to osimertinib, indicating a correlation with treatment response. Oncogenic: The mention of the EGFR L858R variant and its role in the context of advanced LUAD suggests that it contributes to tumor development or progression, particularly as it is associated with resistance mechanisms.
Gene→Variant (gene-first): 2064:D769Y 2064:L755S 1956:L858R 2064:c.1899-32_1909del
Genes: 2064 1956
Variants: D769Y L755S L858R c.1899-32_1909del
Of the 21 unique ERBB2DeltaEx16 variants detected from Chinese patients, 9 involved complete deletion of exon 16, 3 were deletions or point mutations involving splice donors, and 9 deletions or point mutations affecting
[Paragraph-level] PMCID: PMC9859631 Section: RESULTS PassageIndex: 5
Evidence Type(s): Diagnostic, Predictive
Justification: Diagnostic: The passage discusses the detection of ERBB2 variants in patients, indicating their association with specific cases, which supports their use in defining or classifying a disease subtype. Predictive: The mention of the novel variant ERBB2 c.1899-2A>G being detected after treatment suggests a potential correlation with treatment response, indicating its relevance in predicting therapy outcomes.
Gene→Variant (gene-first): 2064:c.1899-2A>G 2064:c.1899-880_1946+761del
Genes: 2064
Variants: c.1899-2A>G c.1899-880_1946+761del
The observation that K-RasG12D and switch 2 insertion mutant proteins are defective for PI3K binding and Akt activation suggested that this might alter effector pathway dependencies. To address this question, we exposed
[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 15
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the sensitivity of cells expressing K-RasG12D to specific therapies, indicating a correlation between the variant and response to treatment with MEK and PI3K inhibitors. Oncogenic: The mention of K-RasG12D in the context of transformed Ba/F3 cells suggests that this somatic variant contributes to tumor development or progression, as it is involved in cytokine-independent growth.
Gene→Variant (gene-first): 3845:K-RasG12D
Genes: 3845
Variants: K-RasG12D
Finally, we tested the effects of the combination therapies on cell proliferation in osimertinib-resistant cell lines. Similar to RPC-9/NaqR cells, the osimertinib-resistant cell lines were derived from RPC-9 cells, desi
[Paragraph-level] PMCID: PMC5792548 Section: RESULTS PassageIndex: 14
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the effects of combination therapies on cell proliferation in osimertinib-resistant cell lines, indicating a relationship between the presence of the T790M mutation and the response to therapy, specifically mentioning osimertinib and naquotinib. Oncogenic: The T790M mutation is maintained in the osimertinib-resistant RPC-9/OsiR cells, suggesting its role in tumor development or progression, particularly in the context of resistance to therapy.
Gene→Variant (gene-first): 1956:C797S 1956:T790M
Genes: 1956
Variants: C797S T790M
Next we investigated RPC-9/NaqR cells, which were derived from gefitinib-resistant lung adenocarcinoma cell lines (RPC-9 cells harboring the EGFR exon 19del and T790M mutations). Exposure to naquotinib inhibited the phos
[Paragraph-level] PMCID: PMC5792548 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses gefitinib-resistant lung adenocarcinoma cell lines harboring the EGFR exon 19del and T790M mutations, indicating a correlation with resistance to therapy, specifically gefitinib. Oncogenic: The mention of the EGFR exon 19del and T790M mutations in the context of gefitinib resistance suggests that these somatic variants contribute to tumor development or progression in lung adenocarcinoma.
Gene→Variant (gene-first): 1956:19del 1956:T790M
Genes: 1956
Variants: 19del T790M
To further examine the role of MET in EGFR-TKI-naive cancer cells, we developed another resistant cell line from EGFR-TKI-naive lung cancer cells, HCC827, which harbor the EGFR exon 19del. The resistant cell line, design
[Paragraph-level] PMCID: PMC5792548 Section: RESULTS PassageIndex: 8
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The passage discusses the role of the EGFR exon 19del variant in the development of a resistant cell line, indicating that this somatic variant contributes to tumor progression and resistance mechanisms in lung cancer cells. Predictive: The passage mentions that the combination of EGFR-TKIs and MET inhibitors showed an excellent inhibitory effect on cell proliferation in the resistant cell line, suggesting a correlation between the variant and response to therapy.
Gene→Variant (gene-first): 1956:19del
Genes: 1956
Variants: 19del
Next, we assessed the effects of several generations of EGFR-TKIs in these naquotinib-resistant cell lines. The resistant cell lines exhibited 52- to 157-fold resistance to naquotinib compared with each parental cell lin
[Paragraph-level] PMCID: PMC5792548 Section: RESULTS PassageIndex: 4
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the acquired EGFR C797S mutation in the context of resistance to osimertinib, indicating that this variant correlates with resistance to a specific therapy. Oncogenic: The C797S mutation is described as contributing to resistance in cell lines, suggesting its role in tumor progression or development in the context of EGFR-TKI treatment.
Gene→Variant (gene-first): 1956:C797S
Genes: 1956
Variants: C797S
First, to explore the mechanism of resistance to naquotinib, we established naquotinib-resistant lung cancer cells using a cell line-based model. The following cell lines were examined: 1. EGFR-TKI-naive PC-9 cells harbo
[Paragraph-level] PMCID: PMC5792548 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the establishment of naquotinib-resistant lung cancer cells and mentions the effectiveness of naquotinib in inhibiting cell proliferation, indicating a correlation between the variants (19del and T790M) and resistance to therapy. Oncogenic: The presence of the T790M mutation in acquired gefitinib-resistant cells suggests that it contributes to tumor development or progression, as it is associated with resistance mechanisms in lung cancer.
Gene→Variant (gene-first): 1956:19del 1956:T790M
Genes: 1956
Variants: 19del T790M
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
We also investigated whether drug efficacy is dependent on the FGFR variants in patients. For this purpose, we retrospectively collected variant information and drug efficacy data related to FGFR inhibitors in 399 cases
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 22
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the correlation between the FGFR3 S249C variant and the response to treatment with FGFR TKIs, indicating that patients with this mutation exhibited partial or complete responses, which aligns with predictive evidence. Oncogenic: The FGFR3 S249C variant is described as the most frequent mutation of FGFR3, suggesting its role in tumor development or progression, which supports its classification as oncogenic.
Gene→Variant (gene-first): 2261:S249C
Genes: 2261
Variants: S249C
More than 400 types of FGFR compound mutations were observed in the COSMIC database, and 34 types of those were reported in more than two samples (Fig. 7a). The most frequent compound mutation is the combination of S249C
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 20
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The passage discusses the transforming activities of FGFR3 S249C compound mutations, indicating that these mutations contribute to tumor development or progression as demonstrated by their evaluation in 3T3 and Ba/F3 cells. Predictive: The passage mentions the sensitivity to E7090 and erdafitinib in relation to the mutations, indicating a correlation with treatment response, which aligns with predictive evidence.
Gene→Variant (gene-first): 2261:K650E 2261:K650M 2261:S249C 2261:Y373C
Genes: 2261
Variants: K650E K650M S249C Y373C
Next, we measured the effectiveness of E7090 and erdafitinib in vivo. Mouse 3T3 fibroblasts expressing FGFR1 N546K, FGFR2 N549K, FGFR3 R248C, FGFR3 K650M, or FGFR3 K650N were injected into nude mice that were subsequentl
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 16
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the effectiveness of E7090 and erdafitinib in treating tumors with specific variants, indicating a correlation between the variants and the response to these therapies. Oncogenic: The variants are described in the context of tumor growth and response to treatment, suggesting that they contribute to tumor development or progression.
Gene→Variant (gene-first): 2261:K650M 2261:K650N 2260:N546K 2263:N549K 2261:R248C
Genes: 2261 2260 2263
Variants: K650M K650N N546K N549K R248C
Inhibition of FGFRs and downstream signaling pathways by FGFR TKIs was evaluated through immunoblot analyses (Fig. 3c). While phosphorylation of FGFR3 K650M was suppressed by E7090 at 100 nM, that of FGFR3 K650N was decr
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 14
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the response of FGFR3 variants K650M and K650N to FGFR TKIs, indicating their sensitivity to specific therapies, which aligns with predictive evidence. Functional: The passage describes the alteration of phosphorylation status of the FGFR3 variants K650M and K650N in response to treatment, indicating a change in molecular function due to the variants.
Gene→Variant (gene-first): 2261:K650M 2261:K650N
Genes: 2261
Variants: K650M K650N
Hierarchical clustering analysis was conducted to evaluate the similarity of FGFR inhibitors and FGFR variants using drug sensitivity data of Fig. 4 (Supplementary Fig. 11). FGFR variants were classified into four cluste
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the sensitivity and resistance of FGFR variants, including N546K and N549D/K, to FGFR inhibitors, indicating a correlation with response to therapy. Oncogenic: The passage mentions that KRAS G12V is part of a cluster composed mainly of oncogenic variants, suggesting its role in tumor development or progression.
Gene→Variant (gene-first): 3845:G12V 2260:N546K 2263:N549D/K
Genes: 3845 2260 2263
Variants: G12V N546K N549D/K
To validate the results of the pooled assay, the respective variants to which drug sensitivity was different among TKIs were further analyzed. Interestingly, in the evaluation with the MANO method, different missense var
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive
Justification: Predictive: The passage discusses how different missense variants at specific amino acid positions in FGFR2 and FGFR3 correlate with varying drug sensitivities to FGFR inhibitors, indicating a relationship between the variants and treatment response.
Gene→Variant (gene-first): 2263:K656 2263:K656E/M 2263:N549 2263:N549D/H
Genes: 2263
Variants: K656 K656E/M N549 N549D/H
The drug sensitivity of transformed FGFR variants was also assessed through the MANO method. The mixture of 3T3 cells expressing different types of FGFR variants were treated with eight different targeted drugs, and drug
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 11
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the drug sensitivity of FGFR variants in response to various targeted therapies, indicating that certain variants are sensitive or resistant to specific inhibitors, which aligns with predictive evidence. Oncogenic: The context of transformed FGFR variants suggests that these somatic mutations contribute to tumor development or progression, particularly as they are assessed for their response to targeted therapies.
Gene→Variant (gene-first): 2264:N535K 2260:N546K 2263:N549D/K 2263:V550L
Genes: 2264 2260 2263
Variants: N535K N546K N549D/K V550L
IDH1 R132H and ATRX KO have similar levels of PARP inhibitor sensitivity.
[Paragraph-level] PMCID: PMC8203843 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Predictive
Justification: Predictive: The passage indicates that IDH1 R132H is associated with sensitivity to PARP inhibitors, which correlates the variant with a specific therapy response.
Gene→Variant (gene-first): 3417:R132H
Genes: 3417
Variants: R132H
FLT3 mutations are the most frequently identified genetic alterations in acute myeloid leukemia (AML) and are associated with poor prognosis. Multiple FLT3 inhibitors are in various stages of clinical evaluation. However
[Paragraph-level] PMCID: PMC8255005 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the resistance of FLT3 mutations, specifically F691L, to FLT3 inhibitors and highlights the efficacy of KX2-391 in overcoming this resistance, indicating a correlation with treatment response. Oncogenic: The FLT3 mutations, including D835 and F691, are described as contributing to tumor development and progression in acute myeloid leukemia (AML), which supports their classification as oncogenic variants.
Gene→Variant (gene-first): 2322:D835 2322:D835Y 2322:F691 2322:F691L
Genes: 2322
Variants: D835 D835Y F691 F691L
In metastatic breast cancer, HER2 activating mutations frequently co-occur with mutations in the PIK3CA, TP53, or E-cadherin genes. Of these co-occurring mutations, HER2 and PIK3CA mutations are the most prevalent gene p
[Paragraph-level] PMCID: PMC10527017 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the resistance of HP breast cancers to the pan-HER tyrosine kinase inhibitor, neratinib, and the effectiveness of combining neratinib with trastuzumab deruxtecan and CDK4/6 inhibitors, indicating a correlation with treatment response. Oncogenic: The study involves genetically engineered mice with the HER2V777L mutation, showing accelerated tumor formation and increased invasion, which supports the notion that this somatic variant contributes to tumor development and progression.
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
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
ALK-break positive non-small cell lung cancer (NSCLC) patients initially respond to crizotinib, but resistance occurs inevitably. In this study we aimed to identify fusion genes in crizotinib resistant tumor samples. Re-
[Paragraph-level] PMCID: PMC4821611 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses ALK mutations (p.C1156Y and p.G1269A) in the context of crizotinib resistance, indicating a correlation between these variants and resistance to the therapy. Oncogenic: The ALK mutations are described as being detected in post-treatment tumor samples, suggesting their contribution to tumor development or progression in the context of crizotinib resistance.
Gene→Variant (gene-first): 238:p.C1156Y 238:p.G1269A
Genes: 238
Variants: p.C1156Y p.G1269A
Mutations in ALK, EGFR and KRAS have been reported to confer resistance against crizotinib. To determine presence of mutations in these genes in the three post-treatment samples, we inspected the RNA-seq bam files in IGV
[Paragraph-level] PMCID: PMC4821611 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses mutations in the ALK gene, specifically p.C1156Y and p.G1269A, which have been reported to confer resistance against crizotinib, indicating a correlation with treatment response. Oncogenic: The presence of mutations in the ALK gene, such as p.C1156Y and p.G1269A, suggests that these somatic variants contribute to tumor development or progression, as they were identified in post-treatment tumor samples.
Gene→Variant (gene-first): 238:c.3467G>A 238:c.3806G>C 238:p.C1156Y 238:p.G1269A
Genes: 238
Variants: c.3467G>A c.3806G>C p.C1156Y p.G1269A
We next examined whether cells expressing wildtype and mutant FGFR3 were responsive to FGF1 stimulation in terms of receptor activation (Figure 4a, Supplementary Figure 5) and signaling (Figure 4b, Supplementary Figure 5
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 19
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the response of cells expressing mutant FGFR3 variants (S249C, Y375C, K652E) to FGF1 stimulation, indicating a correlation with receptor activation and signaling, which relates to treatment response. Functional: The passage describes how the variants S249C, Y375C, and K652E affect the phosphorylation of FGFR3, indicating that these mutations alter the molecular function of the receptor in response to ligand stimulation.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
OS of EGFR-TKI treated patients was similar for 1st and 2nd-line EGFR-TKI treatment. Patients not treated with EGFR-TKI had no benefit in OS. Re-biopsies obtained at progression revealed an EGFR-T790M mutation in 73% (n=
[Paragraph-level] PMCID: PMC5652823 Section: ABSTRACT PassageIndex: 7
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage indicates that patients with the EGFR-T790M mutation responded to the 3rd-generation EGFR-TKI osimertinib, suggesting a correlation between the variant and treatment response. Diagnostic: The EGFR-T790M mutation is mentioned as being revealed in re-biopsies at progression, indicating its role in defining or confirming the presence of a specific disease state in patients treated with EGFR-TKIs.
Gene→Variant (gene-first): 1956:T790M
Genes: 1956
Variants: T790M
BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib are currently the standard treatment for metastatic melanoma with BRAF V600 mutations. However, given the rarity of noncutaneous melanoma, including acral and mu
[Paragraph-level] PMCID: PMC5122709 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the effectiveness of BRAF inhibitors in patients with metastatic melanoma harboring BRAF V600 mutations, indicating a correlation with treatment response. Diagnostic: The BRAF V600 mutation is used to define and classify patients with metastatic melanoma, as all patients in the study had BRAFV600E mutations.
Gene→Variant (gene-first): 673:V600
Genes: 673
Variants: V600
Twenty-seven patients with a median age of 49 years (range 23-82) were treated with BRAF inhibitors. Eleven patients received dabrafenib with trametinib, and 16 were treated with vemurafenib. Patients received 150 mg of
[Paragraph-level] PMCID: PMC5122709 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Diagnostic, Oncogenic
Justification: Predictive: The passage discusses patients treated with BRAF inhibitors, specifically mentioning the BRAF V600E mutation, which correlates with response to these therapies. Diagnostic: The passage states that all patients tested positive for the BRAF V600E mutation, indicating its use in defining or confirming the presence of a specific subtype of melanoma. Oncogenic: The BRAF V600E mutation is implicated in the development of melanoma, suggesting its role as a somatic variant contributing to tumor progression.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
Mutations previously correlated with response were detected in five tumours, four with exon 19 deletions and one with an exon 21 missense L858R point mutation. Increased gene copy number was observed in thirteen tumours,
[Paragraph-level] PMCID: PMC1952070 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses mutations, including the L858R point mutation, in the context of their correlation with response to treatment, indicating a predictive relationship. Diagnostic: The mention of the L858R mutation as part of a group of mutations previously correlated with response suggests its role in defining or classifying a disease subtype.
Gene→Variant (gene-first): 1956:L858R
Genes: 1956
Variants: L858R
Additionally, we predicted relative RAF affinity changes for amino acid substitutions lacking experimental measurements (15 out of 23; Fig. 4B). These include G12S, which we predict has a decreased RAF affinity like othe
[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 16
Evidence Type(s): Functional, Predictive
Justification: Functional: The passage discusses how specific amino acid substitutions affect RAF affinity, indicating that these variants alter molecular function related to protein interactions. Predictive: The passage predicts changes in RAF affinity for various variants, suggesting a correlation with potential therapeutic responses or resistance based on their affinity levels.
Gene→Variant (gene-first): 3265:A146V 673:A18D 3265:A59T 3845:G12 3845:G12S 3845:G13C 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H 3845:Q61P 4893:Q61R 3845:R164Q 22882:T74P
Genes: 3265 673 3845 4893 22882
Variants: A146V A18D A59T G12 G12S G13C G13V K117N L19F Q22K Q61H Q61P Q61R R164Q T74P
In our second approach, we used PHATE dimensionality reduction to score overall similarities among the 935 variants from 7 RAS genes. We performed 1D PHATE (PHATE1) analysis of the 5 computational scores that correlated
[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 13
Evidence Type(s): Functional, Predictive, Oncogenic
Justification: Functional: The passage discusses how mutated KRAS proteins may alter GAP binding and change GAP-mediated hydrolysis rates, indicating that the variants affect molecular function. Predictive: The analysis provides a probability density distribution and suggests that the variants can predict relative levels for mutations based on their GAP-mediated hydrolysis rates, indicating a correlation with functional outcomes. Oncogenic: The context of the variants being associated with cancer and their effects on GAP-mediated hydrolysis suggests that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 3845:A146T 3265:A146V 673:A18D 3265:A59T 3845:G12A/R 3845:G12D 3845:G12S 3845:G13C 3845:G13D 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H 22882:T74P
Genes: 3845 3265 673 22882
Variants: A146T A146V A18D A59T G12A/R G12D G12S G13C G13D G13V K117N L19F Q22K Q61H T74P
Stratification analysis was also performed to evaluate the potential effects of TYMS rs3786362 in mCRC patients in the dominant model. Overall, the carriers of the risk G allele reduced PFS with respect to female, younge
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 15
Evidence Type(s): Prognostic, Predictive
Justification: Prognostic: The passage discusses how the rs3786362 variant correlates with progression-free survival (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC) patients, indicating its association with disease outcomes independent of therapy. Predictive: The passage suggests that TYMS rs3786362 could be a predictive biomarker for survival in mCRC patients, indicating a potential correlation with treatment response in specific subgroups.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
In order to explore the correlation of rs3786362 in TYMS and responses to first-line chemotherapy in mCRC patients, we conducted three models including additive model, dominant model and recessive model for correlation a
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive
Justification: Predictive: The passage discusses the correlation of the variant rs3786362 with responses to first-line chemotherapy in mCRC patients, indicating that the G allele is associated with reduced disease control rate (DCR), which relates to treatment response.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
The correlation between rs3786362 in TYMS and DCR of mCRC patients
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive
Justification: Predictive: The passage discusses the correlation between the variant rs3786362 and the disease control rate (DCR) in metastatic colorectal cancer (mCRC) patients, indicating a relationship with treatment response.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
We analyzed the association between 35 SNPs and PFS of mCRC patients in the additive model after genotyping (Supplementary Table S4). As shown in Table 1, we found that four SNPs (rs369803 in FOLH1, rs10432965 in FTCD, r
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 8
Evidence Type(s): Prognostic, Predictive
Justification: Prognostic: The passage discusses the correlation of SNPs, specifically rs3786362 and rs369803, with progression-free survival (PFS) in metastatic colorectal cancer (mCRC) patients, indicating their association with disease outcome. Predictive: The passage mentions the correlation of SNPs with disease control rate (DCR), suggesting that these variants may influence treatment response in mCRC patients.
Gene→Variant (gene-first): 10841:rs10432965 2346:rs369803 7298:rs3786362 113235:rs4795436
Genes: 10841 2346 7298 113235
Variants: rs10432965 rs369803 rs3786362 rs4795436
The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade >= 3 treatment-emergent adv
[Paragraph-level] PMCID: PMC7325368 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the response of patients with B-RAFV600E mutations to therapy, indicating a correlation between the variant and treatment outcomes in various cancers. Diagnostic: The mention of B-RAFV600E in the context of specific cancer types suggests its use as a biomarker to classify or define these diseases.
Gene→Variant (gene-first): 673:B-RAFV600E
Genes: 673
Variants: B-RAFV600E
Lifirafenib is an investigational, reversible inhibitor of B-RAFV600E, wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and e
[Paragraph-level] PMCID: PMC7325368 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses lifirafenib as an inhibitor specifically targeting B-RAFV600E, indicating a correlation with response to therapy in patients with B-RAF-mutated tumors. Oncogenic: The mention of B-RAFV600E in the context of mutated solid tumors suggests that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 673:B-RAFV600E
Genes: 673
Variants: B-RAFV600E
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
The distribution pattern of the HER2 insertion mutations observed in our cohort was consistent with prior literature. The HER2 Y772_A775dupYVMA mutation was the most frequent and occurred in 65 (72.2%) patients, of whom
[Paragraph-level] PMCID: PMC8887939 Section: RESULTS PassageIndex: 11
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the overall response rate (ORR) and median progression-free survival (PFS) associated with the HER2 insertion mutations, indicating a correlation with treatment response. Diagnostic: The mention of the frequency of the HER2 Y772_A775dupYVMA mutation in patients suggests its role in defining or classifying a specific disease subtype.
Gene→Variant (gene-first): 2064:A775dupYVMA 2064:G776delinsVC
Genes: 2064
Variants: A775dupYVMA G776delinsVC
KRAS G12D-mutant/p53-deficient non-small-cell lung cancer (NSCLC) models are dependent on the NF-kappaB pathway that can be down-regulated by the proteasome inhibitor bortezomib. Two exceptional responders were observed
[Paragraph-level] PMCID: PMC6549573 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the correlation between the KRAS G12D mutation and response to the therapy bortezomib, indicating that exceptional responses can be achieved in patients with this mutation. Oncogenic: The KRAS G12D mutation is described as a somatic variant that contributes to tumor development in non-small-cell lung cancer (NSCLC) models, indicating its role in oncogenesis.
Gene→Variant (gene-first): 3845:G12D
Genes: 3845
Variants: G12D
The core of TAK-788, which is identical to osimertinib, binds in essentially the same manner as osimertinib and the additional isopropyl ester of TAK-788 extends into the back pocket alongside the gatekeeper T790 and sim
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 17
Evidence Type(s): Functional, Predictive
Justification: Functional: The passage discusses how the variant T790 interacts with the drug TAK-788, specifically mentioning hydrogen bonding and binding modes, indicating an alteration in molecular function. Predictive: The mention of TAK-788 binding to T790 suggests a correlation with therapeutic response, as it implies that the presence of T790 may influence the effectiveness of the treatment.
Gene→Variant (gene-first): 1956:T790
Genes: 1956
Variants: T790
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
Somatic mutations in the epidermal growth factor receptor (EGFR) are a major cause of non-small cell lung cancer. Among these structurally diverse alterations, exon 20 insertions represent a unique subset that rarely res
[Paragraph-level] PMCID: PMC11551396 Section: ABSTRACT PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the drug sensitivity and resistance of the exon 20 insertion variants, indicating their correlation with response to specific therapies, particularly EGFR tyrosine kinase inhibitors. Oncogenic: The passage describes somatic mutations in the EGFR gene, specifically the exon 20 insertion variants, which contribute to tumor development in non-small cell lung cancer.
Gene→Variant (gene-first): 1956:L858R 1956:N771insSVD
Genes: 1956
Variants: L858R N771insSVD
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
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
We then tested CHMFL-KIT-031 in the BaF3-TEL-KIT-V559D inoculated mouse model. Through IP injection, the compound displayed a dose-dependent slow down of the tumor progression and 100 mg/kg/day treatment achieved 68.5% t
[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 11
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of the tumor to the treatment with CHMFL-KIT-031, indicating a correlation between the V559D variant and the sensitivity to this specific therapy, as evidenced by tumor growth inhibition. Oncogenic: The V559D variant is implicated in tumor progression, as the passage describes its role in a mouse model where the variant is present and the tumor's response to treatment is evaluated.
Gene→Variant (gene-first): 3815:V559D
Genes: 3815
Variants: V559D
CHMFL-KIT-031 inhibits the tumor growth in BaF3-TEL-KIT-V559D cell inoculated in vivo model
[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 10
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The variant V559D is discussed in the context of tumor growth inhibition, indicating that it contributes to tumor development or progression in the specified cell model. Predictive: The mention of CHMFL-KIT-031 inhibiting tumor growth suggests a correlation between the V559D variant and response to this specific therapy.
Gene→Variant (gene-first): 3815:V559D
Genes: 3815
Variants: V559D
In order to better define CHMFL-KIT-031's inhibitory effect against KIT V559D mutant, we then tested it with purified KIT wt/V559D kinase protein by ADP-Glo assay (Figure 2A). The results showed that it could potently in
[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the inhibitory effect of CHMFL-KIT-031 against the KIT V559D mutant, indicating a correlation with response to therapy, as evidenced by the IC50 values and selectivity over the wild-type KIT. Functional: The variant KIT V559D is shown to alter the molecular function by affecting the phosphorylation of specific sites and downstream mediators, demonstrating its role in biochemical activity as tested in various assays.
Gene→Variant (gene-first): 3815:V559D
Genes: 3815
Variants: V559D
CHMFL-KIT-031 selectively inhibits the KIT V559D mutant over KIT wt
[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 8
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage indicates that CHMFL-KIT-031 selectively inhibits the KIT V559D mutant, suggesting a correlation with response to therapy. Oncogenic: The mention of the KIT V559D mutant in the context of selective inhibition implies that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 3815:V559D
Genes: 3815
Variants: V559D
Then we used the DiscoverX's KINOMEScan platform to further examine CHMFL-KIT-031's kinome-wide selectivity profile. The results showed that it exhibited a great selectivity among 468 kinases/mutants at the concentration
[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the binding and selectivity of CHMFL-KIT-031 to the V559D, L576P, and A829P variants, indicating their potential response to therapy, particularly in the context of inhibitor selectivity. Functional: The results indicate that the variants (V559D, L576P, A829P) alter the binding characteristics of the compound CHMFL-KIT-031, suggesting a change in molecular function related to kinase activity.
Gene→Variant (gene-first): 3815:A829P 3815:L576P 3815:V559D
Genes: 3815
Variants: A829P L576P V559D
Through screening a panel of in-house made structure focused type II lead compounds prepared during development of KIT kinase inhibitors with KIT-V559D permanently transformed BaF3 cells, we found that CHMFL-KIT-031 (Fig
[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of various KIT variants, including V559D, L576P, and others, to different therapies such as CHMFL-KIT-031 and Imatinib, indicating their correlation with treatment sensitivity and resistance. Oncogenic: The variants mentioned, particularly V559D and L576P, are described in the context of their role in transforming BaF3 cells, suggesting that they contribute 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
CHMFL-KIT-031 selectively inhibits the proliferation of BaF3-TEL-KIT-V559D cells
[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage indicates that CHMFL-KIT-031 selectively inhibits the proliferation of cells with the V559D variant, suggesting a correlation with response to this specific therapy. Oncogenic: The mention of the V559D variant in the context of inhibiting cell proliferation implies that it contributes to tumor development or progression, as it is associated with a specific cell line used in cancer research.
Gene→Variant (gene-first): 3815:V559D
Genes: 3815
Variants: V559D
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
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
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
Thirty-two patients with BRAF V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice dai
[Paragraph-level] PMCID: PMC10011885 Section: ABSTRACT PassageIndex: 7
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the overall response rates and clinical benefit rates of patients with BRAF V600E positive metastatic colorectal cancer treated with vemurafenib and erlotinib, indicating a correlation with treatment response. Oncogenic: The mention of BRAF V600E in the context of metastatic colorectal cancer suggests that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While co
[Paragraph-level] PMCID: PMC10011885 Section: ABSTRACT PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the use of BRAF V600E mutant colorectal cancer in the context of therapy, specifically mentioning the effectiveness of combination therapy with BRAF inhibitors and EGFR-targeting antibodies, indicating a correlation with treatment response. Oncogenic: The mention of BRAF V600E in the context of metastatic colorectal cancer suggests that this somatic variant contributes to tumor development or progression, as it is associated with a significant clinical problem in this cancer type.
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
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
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
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
To analyze the response of KB1(L1363P)P mammary tumors to HRR deficiency-targeted therapy, we performed orthotopic transplantations with spontaneous donor tumors as previously described. To capture the heterogeneity of K
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 15
Evidence Type(s): Predictive, Oncogenic, Functional
Justification: Predictive: The passage discusses the response of KB1(L1363P)P mammary tumors to targeted therapies, indicating that these tumors responded significantly better to cisplatin and the PARP inhibitor AZD2461, which correlates the variant with treatment response. Oncogenic: The variant is associated with tumor development and progression, as it is discussed in the context of mammary tumors and their response to therapies, suggesting a role in cancer biology. Functional: The passage describes how the variant affects the ability of tumor cells to induce RAD51 foci in response to gamma-radiation, indicating an alteration in molecular function related to DNA repair mechanisms.
Gene→Variant (gene-first): 7158:L1363P 7158:p.L1363P
Genes: 7158
Variants: L1363P p.L1363P
KB1(L1363P)P mammary tumors respond to cisplatin and PARP inhibition
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 14
Evidence Type(s): Predictive
Justification: Predictive: The variant L1363P is associated with a response to cisplatin and PARP inhibition, indicating its correlation with treatment sensitivity.
Gene→Variant (gene-first): 7158:L1363P
Genes: 7158
Variants: L1363P
To verify whether mouse Brca1 p.L1363P phenocopies human BRCA1 p.L1407P, we analyzed Brca1LP/LP;Trp53Delta/Delta (LP/LP) mutant and Brca1LP/+;Trp53Delta/Delta (LP/+) control MEFs for BRCA1-PALB2 interaction and HRR defec
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses increased sensitivity to cisplatin and PARP1 inhibition in the context of the Brca1 p.L1363P variant, indicating a correlation with treatment response. Functional: The variant p.L1363P is shown to severely attenuate BRCA1-PALB2 binding, which alters the molecular function related to homologous recombination repair (HRR).
Gene→Variant (gene-first): 672:leucine to proline 7158:p.L1363P 672:p.L1407P
Genes: 672 7158
Variants: leucine to proline p.L1363P p.L1407P
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
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 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
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
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
The correlation of inhibition of ALK phosphorylation (Tyr1282/1283) was evaluated as a function of TPX-0131 plasma exposure analysis using the Ba/F3 CDX model harboring the EML4-ALK fusion with the G1202R/L1196M compound
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the correlation of TPX-0131 treatment with tumor growth inhibition and suppression of ALK phosphorylation, indicating that the G1202R, L1196M, and L1198F variants are associated with resistance to therapy and response to treatment. Oncogenic: The variants G1202R, L1196M, and L1198F are described in the context of ALK resistance mutations, suggesting their role in tumor development or progression as they are associated with the EML4-ALK fusion in a cancer model.
Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198F
Genes: 238
Variants: G1202R L1196M L1198F
TGI and the pharmacodynamic modulation of ALK were performed in cell-derived xenograft (CDX) models for clinically relevant ALK mutants that limit the utility of previous generations of ALK inhibitors (e.g. SFM, compound
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 11
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of tumor models harboring specific ALK mutations (G1202R, L1196M, L1198F) to the therapy TPX-0131, indicating a correlation between the variants and treatment efficacy. Oncogenic: The variants G1202R, L1196M, and L1198F are described in the context of tumor models, suggesting that they contribute to tumor development or progression as part of the EML4-ALK fusion.
Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198F
Genes: 238
Variants: G1202R L1196M L1198F
To confirm the results obtained from the cell proliferation assays, TPX-0131 and select other ALK inhibitors were evaluated in assays measuring pharmacodynamic modulation of ALK (autophosphorylation). TPX-0131 suppressed
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how the variants G1202R, L1196M, and L1198F correlate with the response to the ALK inhibitor TPX-0131, indicating their role in resistance to therapy. Oncogenic: The variants mentioned are part of ALK oncogenic fusion proteins, which are implicated in tumor development and progression, as evidenced by their evaluation in assays measuring ALK autophosphorylation.
Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198 238:L1198F
Genes: 238
Variants: G1202R L1196M L1198 L1198F
In cell proliferation assays, TPX-0131 was the most potent inhibitor against a range of EML4-ALK compound mutations (Table 2). TPX-0131 inhibited six of nine compound mutations with IC50 < 1 nmol/L, had IC50 < 10 nmol/L
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 8
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of the ALK G1202R/G1269A/L1204V triple mutation to the TPX-0131 inhibitor, indicating a correlation with treatment sensitivity. Oncogenic: The mention of the EML4-ALK compound mutations, including G1202R, G1269A, and L1204V, in the context of cell proliferation assays suggests that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 238:G1202R 238:G1269A 238:L1204V
Genes: 238
Variants: G1202R G1269A L1204V
To enable comparisons of TPX-0131 with previous generations of ALK inhibitors, a panel of matched cell lines was created that are dependent on ALK resistance mutations found in patients as well as other mutations that ma
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the potency of TPX-0131 against various ALK mutations, indicating that the variant mutations correlate with the response to the therapy, specifically highlighting the differences in inhibition potency against different mutations. Oncogenic: The passage describes the use of engineered Ba/F3 cells expressing oncogenic EML4-ALK variants, indicating that these mutations contribute to tumor development or progression, as they are associated with resistance to ALK inhibitors.
Gene→Variant (gene-first): 238:C1156Y 238:G1202R 238:G1269A 238:G1269S 238:I1171N 238:I1171N/S 238:L1196M 238:L1198F 238:L1204V 238:S/T
Genes: 238
Variants: C1156Y G1202R G1269A G1269S I1171N I1171N/S L1196M L1198F L1204V S/T
Biochemical characterization of TPX-0131 potency against WT and mutant ALK was assessed in a panel of enzymatic assays with recombinant ALK kinase domains performed at 10 muM ATP (Table 1). TPX-0131 potently inhibited WT
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 5
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the potency of TPX-0131 against various ALK mutations, indicating its effectiveness as a therapy for these specific variants, which correlates with treatment response. Functional: The passage describes the biochemical characterization of TPX-0131's inhibition of ALK mutations, focusing on its molecular properties and binding interactions that alter the function of the ALK protein.
Gene→Variant (gene-first): 238:C1156Y 238:D1203N 238:E1210K 238:F1174C 238:F1174L 238:F1174S 238:F1245C 238:G1202 238:G1202R 238:G1269A 238:G1269S 238:I1171N 238:L1152P 238:L1152R 238:L1196M 238:L1198F 238:R1275Q 238:S1206C 238:S1206R 238:T1151-L1152 insT 238:T1151M 238:V1180L
Genes: 238
Variants: C1156Y D1203N E1210K F1174C F1174L F1174S F1245C G1202 G1202R G1269A G1269S I1171N L1152P L1152R L1196M L1198F R1275Q S1206C S1206R T1151-L1152 insT T1151M V1180L
The most prevalent resistance mutations to second-generation ALK inhibitors (e.g., alectinib, brigatinib) are in the solvent front region (e.g., G1202; ref. 16). Molecular modeling illustrates that second-generation ALK
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses resistance mutations, including G1202, in the context of second-generation ALK inhibitors and their reduced potency, indicating a correlation with treatment response. Oncogenic: The mention of G1202 as a resistance mutation suggests that it contributes to tumor development or progression by obstructing binding and reducing the efficacy of ALK inhibitors.
Gene→Variant (gene-first): 238:G1202
Genes: 238
Variants: G1202
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
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
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
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
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
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
In the placebo arm, patients with E545K/E542K mutation had shorter PFS and overall survival than those with wild-type PIK3CA (Supplementary Table 2), suggesting that PIK3CA mutations in the helical domain might play a ro
[Paragraph-level] PMCID: PMC5355930 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive, Prognostic
Justification: Predictive: The passage suggests that patients with E545K/E542K mutations had shorter progression-free survival (PFS) and overall survival, indicating a potential role of these mutations in resistance to hormone therapy. Prognostic: The mention of shorter PFS and overall survival in patients with the E545K/E542K mutations indicates a correlation with disease outcome independent of therapy.
Gene→Variant (gene-first): 5290:E542K 5290:E545K
Genes: 5290
Variants: E542K E545K
To examine the role of domain-specific mutations in PIK3CA on everolimus efficacy, patients were categorised by mutation site, H1047R in the catalytic domain, and E545K and E542K in the helical domain. Everolimus prolong
[Paragraph-level] PMCID: PMC5355930 Section: RESULTS PassageIndex: 8
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the correlation between PIK3CA mutations (H1047R, E545K, E542K) and the efficacy of everolimus, indicating that these variants are associated with prolonged progression-free survival (PFS) in patients treated with this therapy. Oncogenic: The mention of PIK3CA mutations in the context of their role in tumor development and the efficacy of a cancer treatment suggests that these somatic variants contribute to tumor progression.
Gene→Variant (gene-first): 5290:E542K 5290:E545K 5290:H1047R
Genes: 5290
Variants: E542K E545K H1047R
Of the 724 patients in BOLERO-2, 550 patients (76%) underwent PIK3CA cfDNA analysis. The baseline characteristics and clinical outcomes were similar between the cfDNA and overall population (Supplementary Table 1). PIK3C
[Paragraph-level] PMCID: PMC5355930 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Predictive
Justification: Diagnostic: The passage discusses the prevalence of PIK3CA mutations, including specific variants, in a patient population, indicating their association with the disease context. Predictive: The mention of higher prevalence of PIK3CA mutations in the everolimus arm compared to the placebo arm suggests a correlation with treatment response, indicating predictive value.
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
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
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
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
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 human NSCLC cell lines expressing different forms of the EGFR were investigated. Sensitivity of each cell line to the anti-proliferative effect of erlotinib was evaluated by methylene blue assay and is presented in
[Paragraph-level] PMCID: PMC4385014 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the sensitivity of different cell lines to erlotinib treatment, indicating that the presence of the L858R and T790M mutations correlates with reduced sensitivity to the drug, which is a predictive relationship regarding therapy response. Oncogenic: The L858R and T790M mutations are described in the context of their presence in NSCLC cell lines, suggesting their role in tumor development or progression, which aligns with the definition of oncogenic variants.
Gene→Variant (gene-first): 1956:L858R 1956:T790M
Genes: 1956
Variants: L858R T790M
We identified 327 somatic coding mutations, with an average of 55 mutations/tumor (range 34-112), within our cohort ( Table 1 , Figure 1 ). Nonsynonymous single nucleotide variations were the predominant class in all of
[Paragraph-level] PMCID: PMC3923676 Section: RESULTS PassageIndex: 3
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The variant E384X in ERRFI1 is described as being overexpressed in a tumor, indicating its potential role in tumor development or progression. Predictive: The passage discusses the therapeutic relevance of FGFR2 fusions and their treatment with FGFR inhibitors, suggesting a correlation with response to therapy.
Gene→Variant (gene-first): 672:E384X
Genes: 672
Variants: E384X
Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable targets, we examined si
[Paragraph-level] PMCID: PMC3923676 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the use of erlotinib, an EGFR kinase inhibitor, in a patient with the ERRFI1 E384X mutation, noting rapid and robust disease regression, indicating a correlation between the variant and response to therapy. Oncogenic: The E384X variant in ERRFI1 is described as a somatic mutation that inactivates a negative regulator of EGFR activation, suggesting its contribution to tumor development or progression.
Gene→Variant (gene-first): 672:E384X
Genes: 672
Variants: E384X
In one of every four or five cases of breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is overexpressed. These carcinomas are known as HER2-positive. HER2 overexpression is linked to an aggressive
[Paragraph-level] PMCID: PMC7081042 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Diagnostic, Oncogenic
Justification: Predictive: The passage discusses how certain HER2 mutations, such as S310F, S310Y, R678Q, D769H, and I767M, correlate with favorable outcomes and good responses to anti-HER2 therapy, indicating their predictive value for treatment efficacy. Diagnostic: The passage mentions the identification of HER2 SNPs in HER2-positive breast cancer patients and their relationship with clinical outcomes, suggesting that these variants can be used to classify or define the disease subtype. Oncogenic: The passage indicates that somatic mutations in HER2 are linked to resistance to anti-HER2 therapy, suggesting that these mutations contribute to tumor development or progression.
Gene→Variant (gene-first): 2064:D769H 2064:D769Y 2064:I767M 1956:K753I 2064:L755S 2064:R678Q 2064:S310F 2064:S310Y 2064:V842I
Genes: 2064 1956
Variants: D769H D769Y I767M K753I L755S R678Q S310F S310Y V842I
In the BEACON CRC study, encorafenib plus cetuximab improved OS, ORR, and progression-free survival in previously treated patients in the metastatic setting compared with standard chemotherapy. Based on the primary and u
[Paragraph-level] PMCID: PMC8078423 Section: ABSTRACT PassageIndex: 8
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the improved overall survival (OS), objective response rate (ORR), and progression-free survival associated with the treatment of encorafenib plus cetuximab in patients with BRAF V600E mCRC, indicating a correlation with therapy response. Diagnostic: The mention of BRAF V600E in the context of metastatic colorectal cancer (mCRC) suggests its role in defining or classifying a specific disease subtype, as it is associated with a particular treatment regimen.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
In this open-label, phase III trial, 665 patients with BRAF V600E-mutant mCRC were randomly assigned 1:1:1 to receive triplet, doublet, or control. Primary end points were OS and independently reviewed ORR comparing trip
[Paragraph-level] PMCID: PMC8078423 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses a trial involving patients with BRAF V600E-mutant mCRC and mentions endpoints related to overall survival (OS) and objective response rate (ORR), indicating a correlation with treatment response. Diagnostic: The mention of "BRAF V600E-mutant mCRC" implies that the variant is used to classify or define a specific subtype of cancer, which aligns with diagnostic evidence.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
BEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus cetuximab in patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC), afte
[Paragraph-level] PMCID: PMC8078423 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the correlation of the BRAFV600E variant with improved overall survival and objective response rate in patients treated with specific therapies, indicating its predictive value for treatment response. Diagnostic: The mention of BRAFV600E in the context of metastatic colorectal cancer suggests its role in defining or classifying a specific subtype of the disease, supporting its use as a diagnostic marker.
Gene→Variant (gene-first): 673:BRAFV600E
Genes: 673
Variants: BRAFV600E
The data from safety, efficacy, and PK studies suggest that abivertinib dose levels of 150 to 300 mg twice a day may represent the efficacious range while 350 mg twice a day dose had the least favorable safety profile, t
[Paragraph-level] PMCID: PMC9365372 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the overall response rate (ORR) and disease control rate (DCR) in patients with the T790M variant, indicating a correlation with treatment response to abivertinib. Diagnostic: The mention of T790M+ in the context of evaluating patient cohorts suggests that this variant is used to classify or define a specific group of patients for treatment assessment.
Gene→Variant (gene-first): 1956:T790M
Genes: 1956
Variants: T790M
Of the 132 evaluable patients with EGFR T790M+ treated across all dose levels, responses were observed with 100 to 300 mg twice-a-day doses, and with highest ORR in 200 mg twice a day (40.0%, 8/20) and 300 mg twice a day
[Paragraph-level] PMCID: PMC9365372 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive
Justification: Predictive: The passage discusses the response rates of patients with the T790M variant treated with specific doses of abivertinib, indicating a correlation between the variant and treatment response.
Gene→Variant (gene-first): 1956:T790M
Genes: 1956
Variants: T790M
A total of 878 Chinese patients with NSCLC were screened (Fig. 1). In phase I, a total of 231 patients were screened and 140 patients who received treatment were included in this analysis; in phase II, 647 patients were
[Paragraph-level] PMCID: PMC9365372 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Predictive
Justification: Diagnostic: The passage indicates that T790M-negative status was a major reason for exclusion from the study, suggesting its role in defining eligibility for treatment in patients with NSCLC. Predictive: The mention of T790M-negative status as a reason for screening failure implies that the presence of this variant may correlate with resistance to the treatment being studied (abivertinib).
Gene→Variant (gene-first): 1956:T790M
Genes: 1956
Variants: T790M
In this follow-up report, we present updated information regarding a previously reported pediatric patient with a World Health Organization grade I ganglioglioma harboring a BRAF p.T599dup mutation (Cold Spring Harb Mol
[Paragraph-level] PMCID: PMC8040738 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Diagnostic, Oncogenic
Justification: Predictive: The passage discusses the use of combination targeted therapy with a selective BRAF inhibitor and MEK inhibitor for a patient with a BRAF mutation, indicating a correlation with treatment response. Diagnostic: The identification of BRAF alterations is mentioned as a means to assist clinicians in determining alternative targeted treatment strategies, suggesting its role in classifying or defining the tumor type. Oncogenic: The passage implies that the BRAF mutations contribute to tumor development or progression, as the patient has a ganglioglioma harboring a BRAF mutation.
Gene→Variant (gene-first): 673:V600E 673:p.T599dup 673:p.V600E
Genes: 673
Variants: V600E p.T599dup p.V600E
The HDR functional dataset was completely concordant with three other functional studies that evaluated the ability for a human BRCA2 variant to restore survival of Brca2 null mouse embryonic stem cells (Table S1). In an
[Paragraph-level] PMCID: PMC8008494 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the sensitivity of specific BRCA2 variants to PARP inhibitors, indicating a correlation with response to therapy. Functional: The passage describes how the BRCA2 variants influence the ability to restore survival in mouse embryonic stem cells and their functional classification based on drug sensitivity assays.
Gene→Variant (gene-first): 675:c.8723T>G 675:c.8905G>A 675:p.Val2908Gly 675:p.Val2969Met
Genes: 675
Variants: c.8723T>G c.8905G>A p.Val2908Gly p.Val2969Met
It has reported that CREB is a direct target of PTEN where PTEN physically interacts with, and dephosphorylates CREB at Serine 133. Interestingly, cancerous cells have been shown to restore the CREB phosphorylation that
[Paragraph-level] PMCID: PMC6791388 Section: RESULTS PassageIndex: 14
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses how increased phosphorylation of CREB at Ser133 may promote MEK inhibitor resistance, indicating a correlation with treatment response. Functional: The variant at Ser133 is described in the context of altering the phosphorylation state of CREB, which affects its molecular function and activity.
Gene→Variant (gene-first): 7157:S133 7157:Ser133 7157:Serine 133
Genes: 7157
Variants: S133 Ser133 Serine 133
The efficacy of osimertinib against HER2 exon 19, p.L755P mutations and other HER2 exon 19 aberrations should be tested in clinical trials to determine its efficacy as a potential HER2 targeted treatment for patients har
[Paragraph-level] PMCID: PMC10183391 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the efficacy of osimertinib as a potential treatment for patients harboring the p.L755P mutation, indicating a correlation with response to therapy. Diagnostic: The mention of "patients harboring these mutations" suggests that the p.L755P variant is used to classify or define a specific group of patients, indicating its role in diagnosis.
Gene→Variant (gene-first): 2064:p.L755P
Genes: 2064
Variants: p.L755P
Here we demonstrate for the first time in humans, that osimertinib was an effective and well tolerated treatment in a patient with stage IV NSCLC harboring HER2 exon 19, p.L755P mutation.
[Paragraph-level] PMCID: PMC10183391 Section: RESULTS PassageIndex: 5
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage indicates that the p.L755P mutation is associated with an effective response to the treatment with osimertinib in a patient with stage IV NSCLC. Diagnostic: The passage mentions that the patient harbors the p.L755P mutation, which is used to classify the patient's disease subtype (HER2 exon 19 mutation in NSCLC).
Gene→Variant (gene-first): 2064:p.L755P
Genes: 2064
Variants: p.L755P
Osimertinib, a 3rd generation EGFR-TKI has been found in pre-clinical studies, both in vitro and in vivo, to have activity against various HER2 exon 19 aberrations, including HER2 exon 19, p.L755P mutations.
[Paragraph-level] PMCID: PMC10183391 Section: RESULTS PassageIndex: 4
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the activity of Osimertinib against the p.L755P mutation, indicating a correlation with response to therapy. Oncogenic: The mention of the p.L755P mutation in the context of HER2 exon 19 aberrations suggests that it contributes to tumor development or progression, as it is associated with a specific cancer-related mutation.
Gene→Variant (gene-first): 2064:p.L755P
Genes: 2064
Variants: p.L755P
We present a case of a 68-year-old female with stage IV NSCLC harboring a ERBB2 exon 19 c.2262_2264delinsTCC, p.(L755P) mutation treated with osimertinib, resulting in intra- and extracranial response.
[Paragraph-level] PMCID: PMC10183391 Section: RESULTS PassageIndex: 2
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses a patient treated with osimertinib, indicating that the variant correlates with a response to this specific therapy. Diagnostic: The variant is described as being present in a patient with stage IV NSCLC, suggesting its role in defining or classifying the disease.
Gene→Variant (gene-first): 2064:c.2262_2264delinsTCC 2064:p.(L755P)
Genes: 2064
Variants: c.2262_2264delinsTCC p.(L755P)
We analyzed a cohort of MPM samples (n = 29) by DHPLC and sequencing analysis, and identified eight mutations in the tyrosine kinase domain (TKD) of EGFR. Of the 8 mutations in the TK domain, 7 were novel (W731L, E734Q,
[Paragraph-level] PMCID: PMC2970593 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage states that the L858R mutation was found to increase sensitivity to the EGFR inhibitor, Erlotinib, indicating a correlation with treatment response. Oncogenic: All mutations mentioned in the passage, including C797Y, E734Q, E868G, L831H, L858R, T785A, W731L, and Y801H, are described as somatic mutations that contribute to tumor development, as they were identified in the tyrosine kinase domain of EGFR in cancer samples.
Gene→Variant (gene-first): 1956:C797Y 1956:E734Q 1956:E868G 1956:L831H 1956:L858R 1956:T785A 1956:W731L 1956:Y801H
Genes: 1956
Variants: C797Y E734Q E868G L831H L858R T785A W731L Y801H
Since our data indicates that the SF3B1K700E mutation gives rise to an HR defect, we hypothesised that this could be exploited therapeutically to treat tumours that have acquired this mutation. To test this hypothesis, w
[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 19
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how the SF3B1K700E mutation can be therapeutically targeted, indicating a correlation with treatment response to etoposide and olaparib, which are specific therapies. Oncogenic: The SF3B1K700E mutation is implicated in tumor development, as the passage describes its role in creating an HR defect and its effects on tumor growth in xenograft models.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Mutations in SF3B1 have been identified across several cancer types. This key spliceosome component promotes the efficient mRNA splicing of thousands of genes including those with crucial roles in the cellular response t
[Paragraph-level] PMCID: PMC7612475 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Functional
Justification: Predictive: The K700E mutation in SF3B1 increases cellular sensitivity to ionising radiation and various chemotherapeutic agents, including PARP inhibitors, indicating a correlation with treatment response. Functional: The K700E mutation alters HR efficiency and induces unscheduled R-loop formation, replication fork stalling, and defective replication fork restart, demonstrating an impact on molecular function.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Advances in the understanding of the molecular basis for acute myeloid leukemia (AML) have generated new potential targets for treatment. Fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in A
[Paragraph-level] PMCID: PMC5613053 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the ability of gilteritinib to block mutated FLT3, including the D835Y and F691 mutations, and its correlation with improved survival in models of FLT3-driven AML, indicating a response to therapy. Oncogenic: The D835Y and F691 mutations in FLT3 are implicated in the pathogenesis of acute myeloid leukemia (AML), suggesting that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2322:D835Y 2322:F691
Genes: 2322
Variants: D835Y F691
The finding that gilteritinib inhibited FLT3-D835Y and FLT3-ITD-D835Y, both of which harbor mutations in the activation loop essential for binding type 2 inhibitors, suggests that gilteritinib is a type 1 FLT3 inhibitor.
[Paragraph-level] PMCID: PMC5613053 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses how gilteritinib inhibits FLT3-D835Y and FLT3-ITD-D835Y, indicating a correlation between the variant and response to the therapy, which is a predictive context. Functional: The passage describes how gilteritinib interacts with FLT3 at the F691 position and discusses the structural implications of the D835Y mutation, indicating an alteration in molecular function related to the binding of the inhibitor.
Gene→Variant (gene-first): 2322:D835 2322:D835Y 2322:F691
Genes: 2322
Variants: D835 D835Y F691
Since mutations within the TKD of FLT3 (eg, FLT3-D835Y or FLT3-F691) often confer resistance to FLT3 inhibitors that were previously effective against FLT3-ITD, the effect of gilteritinib on these resistance mutations wa
[Paragraph-level] PMCID: PMC5613053 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how mutations such as FLT3-D835Y and FLT3-F691 confer resistance to FLT3 inhibitors, indicating a correlation with treatment response and sensitivity to specific therapies like gilteritinib and quizartinib. Oncogenic: The variants FLT3-D835Y and FLT3-F691 are implicated in tumor development and progression, as evidenced by their expression in Ba/F3 cells and the observed antitumor efficacy of gilteritinib in xenograft models.
Gene→Variant (gene-first): 2322:D835Y 2322:F691 2322:F691 L 2322:F691I
Genes: 2322
Variants: D835Y F691 F691 L F691I
Inhibitory activity of gilteritinib against FLT3 containing ITD +- D835Y or F691 L/I mutations
[Paragraph-level] PMCID: PMC5613053 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the inhibitory activity of gilteritinib against FLT3 containing specific mutations, indicating a correlation with response to therapy. Oncogenic: The mention of D835Y and F691 L/I mutations in the context of FLT3 suggests that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2322:D835Y 2322:F691 L/I
Genes: 2322
Variants: D835Y F691 L/I
To clarify the relationship between CYP3A4 expression and resistance to FOLFIRI and cetuximab, we compared the expression levels of CYP3A4 in CRCs displaying different therapeutic responses (GEO data sets GSE13294 and GS
[Paragraph-level] PMCID: PMC3973211 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the relationship between p53 mutations (including R175H, R248W, R273H, R282W) and resistance to chemotherapy, specifically noting that cells with these mutations showed higher viability and increased IC50 for various drugs, indicating a correlation with drug resistance. Oncogenic: The passage implies that the p53 mutations contribute to tumor behavior by affecting cell response to chemotherapy, suggesting their role in tumor development or progression.
Gene→Variant (gene-first): 7157:R175H 7157:R248W 7157:R273H 7157:R282W
Genes: 7157
Variants: R175H R248W R273H R282W
The GSEA analysis revealed that most of the drug metabolism enzymes in association with p53 R248/R282 mutations are responsible for the clearance of chemotherapeutic drugs. Among these, the most relevant one was cytochro
[Paragraph-level] PMCID: PMC3973211 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the association between p53 mutations (R248, R282) and the expression of CYP3A4, a drug metabolism enzyme, indicating a correlation with drug clearance and potential response to chemotherapeutic drugs. Functional: The passage describes how p53 mutations (R248, R282) alter the expression levels of the CYP3A4 enzyme, demonstrating a change in molecular function related to drug metabolism.
Gene→Variant (gene-first): 7157:R175 7157:R175H 7157:R248 7157:R248W 7157:R273 7157:R273H 7157:R282 7157:R282W
Genes: 7157
Variants: R175 R175H R248 R248W R273 R273H R282 R282W
R248 and R282 mutations associate with drug metabolism enzymes
[Paragraph-level] PMCID: PMC3973211 Section: RESULTS PassageIndex: 7
Evidence Type(s): Diagnostic, Predictive
Justification: Diagnostic: The passage indicates that the R282 mutation is associated with drug metabolism enzymes, suggesting its role in defining or classifying a specific biological context related to drug metabolism. Predictive: The mention of the R282 mutation in relation to drug metabolism enzymes implies a potential correlation with response or sensitivity to therapies that involve these enzymes.
Gene→Variant (gene-first): 7157:R282
Genes: 7157
Variants: R282
Next, we determined whether metformin had superior antitumor activity in KRAS-mutated CRC cell lines to those with KRAS wild type through a cell-viability test. As shown in SI Appendix, Fig. S2A, metformin inhibited the
[Paragraph-level] PMCID: PMC7293710 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how the KRASG12V mutation correlates with increased sensitivity to the antiproliferation therapy of metformin, indicating a predictive relationship between the variant and treatment response. Oncogenic: The KRASG12V mutation is implicated in tumor development as it is mentioned in the context of its effect on cell viability and sensitivity to therapy in colorectal cancer cell lines.
Gene→Variant (gene-first): 3845:G12V
Genes: 3845
Variants: G12V
CDK4/6 inhibition with endocrine therapy is now a standard of care for advanced estrogen receptor positive breast cancer. Mechanisms of CDK4/6 inhibitor resistance have been described pre-clinically, with limited evidenc
[Paragraph-level] PMCID: PMC6368247 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the emergence of the ESR1 Y537S mutation in the context of resistance to CDK4/6 inhibitors, indicating a correlation with treatment response and resistance. Oncogenic: The mention of the ESR1 Y537S mutation as a new driver mutation suggests that it contributes to tumor development or progression, particularly in the context of breast cancer.
Gene→Variant (gene-first): 5728:Y537S
Genes: 5728
Variants: Y537S
Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-mole
[Paragraph-level] PMCID: PMC9900321 Section: ABSTRACT PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in treating pancreatic ductal adenocarcinoma, indicating a correlation between the Gly-to-Asp mutation and response to therapy. Oncogenic: The Gly-to-Asp mutation in the KRAS oncogene is described as contributing to tumor development in pancreatic ductal adenocarcinoma, as it is found in more than 90% of patients with this cancer type.
Gene→Variant (gene-first): 3845:Gly-to-Asp
Genes: 3845
Variants: Gly-to-Asp
Mutation of several genes, most notably TP53 or ASXL1 transcriptional regulator 1 (ASXL1), were shown to cause a broad pattern of drug resistance. Interestingly, a few drugs trended more sensitive to TP53 mutant cases, s
[Paragraph-level] PMCID: PMC6280667 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive
Justification: Predictive: The passage discusses the correlation of mutations, including those in splicing components like ZRSR2, with sensitivity to various drugs, indicating a relationship between the variant and treatment response.
Gene→Variant (gene-first): 8233:serine/arginine
Genes: 8233
Variants: serine/arginine
HOXC10 is overexpressed in 51% of primary KRAS-mutant tumors (Figure 3A; TCGA, >= 2SD over expression in normal lung), consistent with observations in cell lines (Figure 2B). By analyzing KRAS-mutant tumor/normal matched
[Paragraph-level] PMCID: PMC10805385 Section: RESULTS PassageIndex: 17
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The passage discusses the overexpression of HOXC10 in KRAS-mutant tumors, specifically mentioning the genotype KRAS G12C/TP53 G245V, indicating that these somatic variants contribute to tumor development or progression. Predictive: The passage mentions the efficacy of combined MEK/BET inhibitors causing tumor regression in KRAS-mutant patient-derived xenograft models, suggesting a correlation between the variants and response to therapy.
Gene→Variant (gene-first): 3845:G12C 7157:G245V
Genes: 3845 7157
Variants: G12C G245V
This drug combination was also tested on NCI "Rasless" MEFs carrying KRASG12C or KRASG12D mutations. KPT9274 synergized with MRTX849 at all dose combinations yielding suppressed growth of KRASG12C-mutant MEFs (Supplement
[Paragraph-level] PMCID: PMC10690049 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of KRASG12D mutant MEFs to a drug combination, indicating that the variant is associated with resistance to growth inhibition by the therapies tested. Oncogenic: The KRASG12D variant is implicated in tumor behavior, as it is described in the context of MEFs (mouse embryonic fibroblasts) and their growth characteristics, suggesting a role in tumor development or progression.
Gene→Variant (gene-first): 3845:G12D
Genes: 3845
Variants: G12D
KRAS G12C-mutant MIA PaCa-2 (PDAC) and NCI-H358 (NSCLC) cells were exposed to MRTX849/AMG510 and KPT9274 at different dose combinations. As shown in Fig. 2A and B, all three dose combinations tested demonstrated synergis
[Paragraph-level] PMCID: PMC10690049 Section: RESULTS PassageIndex: 6
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of KRAS G12C-mutant cells to specific therapies, indicating a correlation between the variant and sensitivity to the drugs MRTX849/AMG510 and KPT9274. Oncogenic: The variant KRAS G12C is implicated in tumor development, as the passage describes its presence in cancer cell lines and their proliferation in response to treatment, suggesting a role in cancer progression.
Gene→Variant (gene-first): 3845:G12C
Genes: 3845
Variants: G12C
Somatic mutations found within the tyrosine kinase domain (TKD) of the human epidermal growth factor (HER) family of receptors have been implicated in the development and progression of non-small cell lung cancer (NSCLC)
[Paragraph-level] PMCID: PMC4823091 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Oncogenic, Predictive, Functional
Justification: Oncogenic: The passage discusses the HER3 V855A somatic mutation's role in the development and progression of non-small cell lung cancer (NSCLC), indicating its contribution to tumor behavior. Predictive: The text mentions that HER-targeted inhibitors potently suppress mutant HER3 activity, suggesting a correlation between the V855A variant and response to targeted therapies. Functional: The passage states that in silico computational modeling predicts that the V855A mutation alters the kinase domain and c-terminal end of the HER3 protein, indicating a change in molecular function.
Gene→Variant (gene-first): 324:V855A
Genes: 324
Variants: V855A
We further examined the effects of the inhibitors on HER-related signaling activity and survival using the Ba/F3 model system. Afatinib (100nmol/L) potently inhibited NRG1beta-induced phosphorylation of HER3, wild type H
[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 23
Evidence Type(s): Predictive
Justification: Predictive: The passage indicates that tumors harboring HER3-V855A may predict response to targeted therapy, suggesting a correlation between the variant and treatment response.
Gene→Variant (gene-first): 324:V855A
Genes: 324
Variants: V855A
To assess the effect of the inhibitors on colony formation, Ba/F3 co-transfectants were seeded onto methyl-cellulose and treated with HER inhibitors in the presence of NRG1beta. As shown in Fig 6b, afatinib (100 nmol/L)
[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 22
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the effectiveness of HER inhibitors on colony formation in the presence of the V855A variant, indicating a correlation with response to therapy. Oncogenic: The V855A variant is mentioned in the context of colony formation assays, suggesting it contributes to tumor development or progression.
Gene→Variant (gene-first): 324:V855A
Genes: 324
Variants: V855A
To investigate whether HER3-V855A can be therapeutically targeted; we examined the growth inhibitory effects of inhibitors targeting the extracellular and kinase domain of the HER receptors. These inhibitors include: erl
[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 21
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the growth inhibitory effects of various inhibitors on cells expressing the HER3-V855A variant, indicating a correlation between the variant and response to specific therapies, such as afatinib and erlotinib. Functional: The variant HER3-V855A is examined in the context of its effect on cell growth and response to inhibitors, suggesting that it alters the molecular function of the HER3 receptor in relation to drug sensitivity.
Gene→Variant (gene-first): 324:V855A
Genes: 324
Variants: V855A