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    1. karim2001khoury 19 Feb 2026
      Genomic Profiling of KRAS/NRAS/BRAF/PIK3CA Wild-Type Metastatic Colorectal Cancer Patients Reveals Novel Mutations in Genes Potentially Associated with Resistance to Anti-EGFR Agents

      [Paper-level Aggregated] PMCID: PMC6627713

      Evidence Type(s): Oncogenic, Prognostic, Functional

      Justification: Oncogenic: Several variants, including those in the TP53 and APC genes, are associated with cancer development, and specific mutations like p.Arg505Cys in FBXW7 have been reported to lead to loss of function, contributing to oncogenesis. Prognostic: The presence of certain variants, such as those in MAP2K1 and FBXW7, correlates with progression-free survival (PFS) outcomes, indicating their potential role in predicting disease progression. Functional: The variant p.Lys57Glu in MAP2K1 is associated with a gain of function of the MEK1 protein, indicating a functional impact on protein activity that may influence cancer pathways.

      Gene→Variant (gene-first): FBXW7(55294):c.1268G>T FBXW7(55294):p.Gly423Val FBXW7(55294):c.1513C>T EGFR(1956):c.1798G>A FBXW7(55294):p.Arg505Cys BRAF(673):p.Asp600Asn MAP2K1(5604):c.169A>G MAP2K1(5604):c.199G>A MAP2K1(5604):p.Asp67Asn MAP2K1(5604):p.Lys57Glu KRAS(3845):c.183A>T KRAS(3845):p.Gln61His TP53(7157):c.275_276insGGCC APC(324):c.4098_4099delTCinsAT APC(324):c.4467_4468insCATTTTG APC(324):c.589_590insGAGTT APC(324):c.837_838InsG NF1(4763):c.5101A>T NF1(4763):c.638_639insA NF1(4763):p.Asn214Lys fs*2 NF1(4763):p.Lys1701Ter

      Genes: FBXW7(55294) EGFR(1956) BRAF(673) MAP2K1(5604) KRAS(3845) TP53(7157) APC(324) NF1(4763)

      Variants: c.1268G>T p.Gly423Val c.1513C>T c.1798G>A p.Arg505Cys p.Asp600Asn c.169A>G c.199G>A p.Asp67Asn p.Lys57Glu c.183A>T p.Gln61His c.275_276insGGCC c.4098_4099delTCinsAT c.4467_4468insCATTTTG c.589_590insGAGTT c.837_838InsG c.5101A>T c.638_639insA p.Asn214Lys fs*2 p.Lys1701Ter

      CIViC paper-level aggregated PMC6627713
    2. karim2001khoury 19 Feb 2026
      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

      CIViC paragraph-level PMC6627713 Diagnostic Prognostic Predictive Oncogenic
    3. karim2001khoury 19 Feb 2026
      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

      CIViC paragraph-level PMC6627713 Predictive Diagnostic
    4. karim2001khoury 19 Feb 2026
      Of the three missense mutations detected in FBXW7, two were found in patients with a PFS shorter than median PFS. Patient P14 (PFS 8.07 months) carried the c.1798G>A variant (p.Asp600Asn) and patient P18 (PFS 1.73 months

      [Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 14

      Evidence Type(s): Prognostic, Oncogenic

      Justification: Prognostic: The passage indicates that two missense mutations are associated with patients having a shorter progression-free survival (PFS), suggesting a correlation with disease outcome. Oncogenic: The FBXW7 p.Arg505Cys mutation is reported to lead to loss of function of the protein and has been associated with several cancer types, indicating its contribution to tumor development or progression.

      Gene→Variant (gene-first): 55294:c.1513C>T 1956:c.1798G>A 55294:p.Arg505Cys 673:p.Asp600Asn

      Genes: 55294 1956 673

      Variants: c.1513C>T c.1798G>A p.Arg505Cys p.Asp600Asn

      CIViC paragraph-level PMC6627713 Prognostic Oncogenic
    5. karim2001khoury 19 Feb 2026
      Two patients (P20 and P21) had variants in NF1, a negative regulator of RAS, inactivated by mutation in various cancers. Specifically, we found an insertion (c.638_639insA; p.Asn214Lys fs*2) in the tumor from patient P20

      [Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 13

      Evidence Type(s): Oncogenic, Prognostic

      Justification: Oncogenic: The variants in NF1 are described as contributing to tumor development by leading to a loss of function and increased activation of the RAS signaling pathway, indicating their role in oncogenesis. Prognostic: The passage provides progression-free survival (PFS) times for the patients with the variants, suggesting a correlation between the variants and disease outcome.

      Gene→Variant (gene-first): 4763:c.5101A>T 4763:c.638_639insA 4763:p.Asn214Lys fs*2 4763:p.Lys1701Ter

      Genes: 4763

      Variants: c.5101A>T c.638_639insA p.Asn214Lys fs*2 p.Lys1701Ter

      CIViC paragraph-level PMC6627713 Oncogenic Prognostic
    6. karim2001khoury 19 Feb 2026
      Patient P3 (PFS 6.63 months) carried the variant c.169A>G in the MAP2K1 gene coding for the MEK1 protein. This variant has been already reported in the cBioPortal database. It results in the substitution of an amino acid

      [Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The variant c.169A>G results in an amino acid substitution (p.Lys57Glu) that is associated with a gain of function of the MEK1 protein, indicating an alteration in molecular function. Oncogenic: The variant is discussed in the context of its role in the MAP2K1 gene, which is known to contribute to tumor development or progression, suggesting its oncogenic potential.

      Gene→Variant (gene-first): 5604:c.169A>G 5604:p.Lys57Glu

      Genes: 5604

      Variants: c.169A>G p.Lys57Glu

      CIViC paragraph-level PMC6627713 Functional Oncogenic
    7. karim2001khoury 19 Feb 2026
      All variants were at an allelic frequency >5% with the exception of a KRAS variant (c.183A>T; p.Gln61His) that was identified in the tumor tissue from patient P7 (PFS 3.93 months) at an allelic frequency of 0.4%. This va

      [Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 11

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage discusses the KRAS variant (c.183A>T; p.Gln61His) identified in tumor tissue, indicating its role in tumor development or progression as it is associated with a specific patient's tumor.

      Gene→Variant (gene-first): 3845:c.183A>T 3845:p.Gln61His

      Genes: 3845

      Variants: c.183A>T p.Gln61His

      CIViC paragraph-level PMC6627713 Oncogenic
    8. karim2001khoury 19 Feb 2026
      Of the 54 SNVs and insertions/deletions (Indels) identified, 35% and 41% were APC and TP53 variants, respectively (Figure 1). Nineteen patients (90.47%) had at least one TP53 SNV or Indel, whereas 15/21 (71.43%) patients

      [Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Diagnostic, Oncogenic

      Justification: Diagnostic: The passage discusses the presence of specific variants in patients and their association with APC and TP53 mutations, indicating their role in defining or classifying the disease context. Oncogenic: The variants mentioned are associated with tumors, suggesting that they contribute to tumor development or progression, which aligns with the definition of oncogenic variants.

      Gene→Variant (gene-first): 7157:c.275_276insGGCC 324:c.4098_4099delTCinsAT 324:c.4467_4468insCATTTTG 324:c.589_590insGAGTT 324:c.837_838InsG

      Genes: 7157 324

      Variants: c.275_276insGGCC c.4098_4099delTCinsAT c.4467_4468insCATTTTG c.589_590insGAGTT c.837_838InsG

      CIViC paragraph-level PMC6627713 Diagnostic Oncogenic
    9. karim2001khoury 19 Feb 2026
      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

      CIViC paragraph-level PMC6627713 Diagnostic Prognostic Predictive Oncogenic
    10. karim2001khoury 19 Feb 2026
      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

      CIViC paragraph-level PMC6627713 Predictive Diagnostic
    11. karim2001khoury 19 Feb 2026
      Of the three missense mutations detected in FBXW7, two were found in patients with a PFS shorter than median PFS. Patient P14 (PFS 8.07 months) carried the c.1798G>A variant (p.Asp600Asn) and patient P18 (PFS 1.73 months

      [Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 14

      Evidence Type(s): Prognostic, Oncogenic

      Justification: Prognostic: The passage indicates that two missense mutations are associated with patients having a shorter progression-free survival (PFS), suggesting a correlation with disease outcome. Oncogenic: The FBXW7 p.Arg505Cys mutation is reported to lead to loss of function of the protein and has been associated with several cancer types, indicating its contribution to tumor development or progression.

      Gene→Variant (gene-first): 55294:c.1513C>T 1956:c.1798G>A 55294:p.Arg505Cys 673:p.Asp600Asn

      Genes: 55294 1956 673

      Variants: c.1513C>T c.1798G>A p.Arg505Cys p.Asp600Asn

      CIViC paragraph-level PMC6627713 Prognostic Oncogenic
    12. karim2001khoury 19 Feb 2026
      Two patients (P20 and P21) had variants in NF1, a negative regulator of RAS, inactivated by mutation in various cancers. Specifically, we found an insertion (c.638_639insA; p.Asn214Lys fs*2) in the tumor from patient P20

      [Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 13

      Evidence Type(s): Oncogenic, Prognostic

      Justification: Oncogenic: The variants in NF1 are described as contributing to tumor development by leading to a loss of function and increased activation of the RAS signaling pathway, indicating their role in oncogenesis. Prognostic: The passage provides progression-free survival (PFS) times for the patients with the variants, suggesting a correlation between the variants and disease outcome.

      Gene→Variant (gene-first): 4763:c.5101A>T 4763:c.638_639insA 4763:p.Asn214Lys fs*2 4763:p.Lys1701Ter

      Genes: 4763

      Variants: c.5101A>T c.638_639insA p.Asn214Lys fs*2 p.Lys1701Ter

      CIViC paragraph-level PMC6627713 Oncogenic Prognostic
    13. karim2001khoury 19 Feb 2026
      Patient P3 (PFS 6.63 months) carried the variant c.169A>G in the MAP2K1 gene coding for the MEK1 protein. This variant has been already reported in the cBioPortal database. It results in the substitution of an amino acid

      [Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The variant c.169A>G results in an amino acid substitution (p.Lys57Glu) that is associated with a gain of function of the MEK1 protein, indicating an alteration in molecular function. Oncogenic: The variant is discussed in the context of its role in the MAP2K1 gene, which is known to contribute to tumor development or progression, suggesting its oncogenic potential.

      Gene→Variant (gene-first): 5604:c.169A>G 5604:p.Lys57Glu

      Genes: 5604

      Variants: c.169A>G p.Lys57Glu

      CIViC paragraph-level PMC6627713 Functional Oncogenic
    14. karim2001khoury 19 Feb 2026
      All variants were at an allelic frequency >5% with the exception of a KRAS variant (c.183A>T; p.Gln61His) that was identified in the tumor tissue from patient P7 (PFS 3.93 months) at an allelic frequency of 0.4%. This va

      [Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 11

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage discusses the KRAS variant (c.183A>T; p.Gln61His) identified in tumor tissue, indicating its role in tumor development or progression as it is associated with a specific patient's tumor.

      Gene→Variant (gene-first): 3845:c.183A>T 3845:p.Gln61His

      Genes: 3845

      Variants: c.183A>T p.Gln61His

      CIViC paragraph-level PMC6627713 Oncogenic
    15. karim2001khoury 19 Feb 2026
      Of the 54 SNVs and insertions/deletions (Indels) identified, 35% and 41% were APC and TP53 variants, respectively (Figure 1). Nineteen patients (90.47%) had at least one TP53 SNV or Indel, whereas 15/21 (71.43%) patients

      [Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Diagnostic, Oncogenic

      Justification: Diagnostic: The passage discusses the presence of specific variants in patients and their association with APC and TP53 mutations, indicating their role in defining or classifying the disease context. Oncogenic: The variants mentioned are associated with tumors, suggesting that they contribute to tumor development or progression, which aligns with the definition of oncogenic variants.

      Gene→Variant (gene-first): 7157:c.275_276insGGCC 324:c.4098_4099delTCinsAT 324:c.4467_4468insCATTTTG 324:c.589_590insGAGTT 324:c.837_838InsG

      Genes: 7157 324

      Variants: c.275_276insGGCC c.4098_4099delTCinsAT c.4467_4468insCATTTTG c.589_590insGAGTT c.837_838InsG

      CIViC paragraph-level PMC6627713 Diagnostic Oncogenic
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    pmc.ncbi.nlm.nih.gov/articles/PMC6627713/pdf/cancers-11-00859.pdf