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    1. karim2001khoury 19 Feb 2026
      Breast cancer mutations HER2V777L and PIK3CAH1047R activate the p21-CDK4/6 –Cyclin D1 axis driving tumorigenesis and drug resistance

      [Paper-level Aggregated] PMCID: PMC10527017

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

      Justification: Oncogenic: The HER2V777L and PIK3CAH1047R mutations are described as activating mutations that promote tumor formation and aggressive cancer characteristics, indicating their role in oncogenesis. Functional: The study demonstrates that the combination of HER2V777L and PIK3CAH1047R mutations enhances cellular migration and invasion, which are functional properties associated with metastatic cancer. Predictive: The findings suggest that the presence of HER2V777L and PIK3CAH1047R mutations can predict the effectiveness of specific drug combinations, such as neratinib plus trastuzumab deruxtecan, in treating breast cancer. Prognostic: The study indicates that the co-occurrence of HER2 and PIK3CA mutations is associated with accelerated tumor growth and metastasis, which can serve as a prognostic indicator for disease progression in breast cancer patients.

      Gene→Variant (gene-first): ERBB2(2064):G776insYVMA ERBB2(2064):V777L PIK3CA(5290):H1047R

      Genes: ERBB2(2064) PIK3CA(5290)

      Variants: G776insYVMA V777L H1047R

      CIViC paper-level aggregated PMC10527017
    2. karim2001khoury 19 Feb 2026
      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

      CIViC paragraph-level PMC10527017 Predictive Oncogenic
    3. karim2001khoury 19 Feb 2026
      To understand whether trends observed in mouse tumors are also found in human disease, we next examined the HER2 and PIK3CA mutations in available TCGA RNA-seq data. We examined data available from 113 normal solid tissu

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 25

      Evidence Type(s): Diagnostic, Oncogenic

      Justification: Diagnostic: The passage discusses the association of the H1047R PIK3CA mutation with specific tumor subtypes, indicating its role in classifying or defining disease characteristics in human samples. Oncogenic: The H1047R PIK3CA mutation is mentioned in the context of tumor analysis, suggesting its contribution to tumor development or progression as it is examined alongside other mutations in cancer samples.

      Gene→Variant (gene-first): 5290:H1047R

      Genes: 5290

      Variants: H1047R

      CIViC paragraph-level PMC10527017 Diagnostic Oncogenic
    4. karim2001khoury 19 Feb 2026
      Consistent with the proteomic data, pathway analysis showed that these genes were enriched for the PIK3-Akt-mTOR signaling pathway (Fig. 6B). The GSEA analysis showed that the mTOR pathway and the MYC target signature we

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 22

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage indicates that the co-expression of the HER2V777L variant contributes to tumorigenesis by amplifying signaling pathways, suggesting its role in tumor development.

      Gene→Variant (gene-first): 2064:V777L

      Genes: 2064

      Variants: V777L

      CIViC paragraph-level PMC10527017 Oncogenic
    5. karim2001khoury 19 Feb 2026
      We next examined gene expression changes using RNA sequencing. We established organoids from H, P, and HP mice tumors and normal mammary glands from WT littermate mice and performed RNA sequencing analysis on 16 independ

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 20

      Evidence Type(s): None

      Justification: Not enough information in this passage.

      Gene→Variant (gene-first): 2064:V777L

      Genes: 2064

      Variants: V777L

      CIViC paragraph-level PMC10527017
    6. karim2001khoury 19 Feb 2026
      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

      CIViC paragraph-level PMC10527017 Functional Predictive
    7. karim2001khoury 19 Feb 2026
      In order to characterize the mechanism causing the rapid breast cancer growth in HP mice, we measured protein phosphorylation using proteomics. We examined the key signaling pathways using the Human/Mouse AKT Pathway Pho

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 17

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the HER2V777L variant enhances cell proliferation by altering the phosphorylation of key proteins involved in the cell cycle, indicating a change in molecular function. Oncogenic: The evidence suggests that the HER2V777L variant contributes to tumor development and progression by promoting aggressive growth in the transgenic mouse model.

      Gene→Variant (gene-first): 2064:V777L

      Genes: 2064

      Variants: V777L

      CIViC paragraph-level PMC10527017 Functional Oncogenic
    8. karim2001khoury 19 Feb 2026
      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

      CIViC paragraph-level PMC10527017 Predictive Oncogenic
    9. karim2001khoury 19 Feb 2026
      We hypothesized that the HER2V777L mutation plays a vital role in metastatic breast cancer. To test this, H, P and HP mice were examined for metastasis to the lung or liver. Metastasis were not seen in HP mice likely bec

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 9

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses the HER2V777L mutation's role in metastatic breast cancer, indicating that it contributes to tumor development and progression, particularly in the context of lung metastasis observed in transgenic mice. Functional: The passage implies that the HER2V777L mutation alters the behavior of breast tumor cells, as evidenced by the invasive phenotype observed in vitro and the specific uptake of the NIR-trastuzumab imaging agent in tumor sites.

      Gene→Variant (gene-first): 2064:V777L

      Genes: 2064

      Variants: V777L

      CIViC paragraph-level PMC10527017 Oncogenic Functional
    10. karim2001khoury 19 Feb 2026
      Lung metastases in HER2V777L transgenic mice and HP organoid transplant mice

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The mention of "Lung metastases in HER2V777L transgenic mice" suggests that the V777L variant contributes to tumor development or progression in a model organism, indicating its oncogenic potential.

      Gene→Variant (gene-first): 2064:V777L

      Genes: 2064

      Variants: V777L

      CIViC paragraph-level PMC10527017 Oncogenic
    11. karim2001khoury 19 Feb 2026
      We isolated breast organoids from WT, H, P, HP mice (Fig. 2A) in order to obtain an enriched epithelial cell population. To assess the cellular migration and invasion signature of HER2V777L and PIK3CAH1047R breast epithe

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses how the combination of HP mutations, including HER2V777L, promotes cancer cell invasion and migration, indicating a role in tumor development or progression. Functional: The passage describes the effects of the HER2V777L variant on cellular migration and invasion, suggesting that it alters molecular or biochemical functions related to these processes.

      Gene→Variant (gene-first): 2064:V777L

      Genes: 2064

      Variants: V777L

      CIViC paragraph-level PMC10527017 Oncogenic Functional
    13. karim2001khoury 19 Feb 2026
      We previously reported the development of a novel transgenic mouse that conditionally expresses the human HER2 V777L cDNA (abbreviated as "H"), which is inserted into the Rosa26 locus using TALEN-based genome editing. Ou

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage describes the PIK3CA H1047R variant as a gain-of-function allele and activating mutation commonly found in human breast cancers, indicating its role in tumor development or progression.

      Gene→Variant (gene-first): 5290:H1047R 2064:V777L

      Genes: 5290 2064

      Variants: H1047R V777L

      CIViC paragraph-level PMC10527017 Oncogenic
    14. karim2001khoury 19 Feb 2026
      Tumor formation in mice with HER2V777L and PIK3CAH1047R

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 2

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage indicates that the HER2V777L variant is involved in tumor formation in mice, suggesting it contributes to tumor development or progression.

      Gene→Variant (gene-first): 2064:V777L

      Genes: 2064

      Variants: V777L

      CIViC paragraph-level PMC10527017 Oncogenic
    15. karim2001khoury 19 Feb 2026
      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

      CIViC paragraph-level PMC10527017 Predictive Oncogenic
    16. karim2001khoury 19 Feb 2026
      To understand whether trends observed in mouse tumors are also found in human disease, we next examined the HER2 and PIK3CA mutations in available TCGA RNA-seq data. We examined data available from 113 normal solid tissu

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 25

      Evidence Type(s): Diagnostic, Oncogenic

      Justification: Diagnostic: The passage discusses the association of the H1047R PIK3CA mutation with specific tumor subtypes, indicating its role in classifying or defining disease characteristics in human samples. Oncogenic: The H1047R PIK3CA mutation is mentioned in the context of tumor analysis, suggesting its contribution to tumor development or progression as it is examined alongside other mutations in cancer samples.

      Gene→Variant (gene-first): 5290:H1047R

      Genes: 5290

      Variants: H1047R

      CIViC paragraph-level PMC10527017 Diagnostic Oncogenic
    17. karim2001khoury 19 Feb 2026
      Consistent with the proteomic data, pathway analysis showed that these genes were enriched for the PIK3-Akt-mTOR signaling pathway (Fig. 6B). The GSEA analysis showed that the mTOR pathway and the MYC target signature we

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 22

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage indicates that the co-expression of the HER2V777L variant contributes to tumorigenesis by amplifying signaling pathways, suggesting its role in tumor development.

      Gene→Variant (gene-first): 2064:V777L

      Genes: 2064

      Variants: V777L

      CIViC paragraph-level PMC10527017 Oncogenic
    18. karim2001khoury 19 Feb 2026
      We next examined gene expression changes using RNA sequencing. We established organoids from H, P, and HP mice tumors and normal mammary glands from WT littermate mice and performed RNA sequencing analysis on 16 independ

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 20

      Evidence Type(s): None

      Justification: Not enough information in this passage.

      Gene→Variant (gene-first): 2064:V777L

      Genes: 2064

      Variants: V777L

      CIViC paragraph-level PMC10527017
    19. karim2001khoury 19 Feb 2026
      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

      CIViC paragraph-level PMC10527017 Functional Predictive
    20. karim2001khoury 19 Feb 2026
      In order to characterize the mechanism causing the rapid breast cancer growth in HP mice, we measured protein phosphorylation using proteomics. We examined the key signaling pathways using the Human/Mouse AKT Pathway Pho

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 17

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the HER2V777L variant enhances cell proliferation by altering the phosphorylation of key proteins involved in the cell cycle, indicating a change in molecular function. Oncogenic: The evidence suggests that the HER2V777L variant contributes to tumor development and progression by promoting aggressive growth in the transgenic mouse model.

      Gene→Variant (gene-first): 2064:V777L

      Genes: 2064

      Variants: V777L

      CIViC paragraph-level PMC10527017 Functional Oncogenic
    21. karim2001khoury 19 Feb 2026
      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

      CIViC paragraph-level PMC10527017 Predictive Oncogenic
    22. karim2001khoury 19 Feb 2026
      We hypothesized that the HER2V777L mutation plays a vital role in metastatic breast cancer. To test this, H, P and HP mice were examined for metastasis to the lung or liver. Metastasis were not seen in HP mice likely bec

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 9

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses the HER2V777L mutation's role in metastatic breast cancer, indicating that it contributes to tumor development and progression, particularly in the context of lung metastasis observed in transgenic mice. Functional: The passage implies that the HER2V777L mutation alters the behavior of breast tumor cells, as evidenced by the invasive phenotype observed in vitro and the specific uptake of the NIR-trastuzumab imaging agent in tumor sites.

      Gene→Variant (gene-first): 2064:V777L

      Genes: 2064

      Variants: V777L

      CIViC paragraph-level PMC10527017 Oncogenic Functional
    23. karim2001khoury 19 Feb 2026
      Lung metastases in HER2V777L transgenic mice and HP organoid transplant mice

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The mention of "Lung metastases in HER2V777L transgenic mice" suggests that the V777L variant contributes to tumor development or progression in a model organism, indicating its oncogenic potential.

      Gene→Variant (gene-first): 2064:V777L

      Genes: 2064

      Variants: V777L

      CIViC paragraph-level PMC10527017 Oncogenic
    24. karim2001khoury 19 Feb 2026
      We isolated breast organoids from WT, H, P, HP mice (Fig. 2A) in order to obtain an enriched epithelial cell population. To assess the cellular migration and invasion signature of HER2V777L and PIK3CAH1047R breast epithe

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses how the combination of HP mutations, including HER2V777L, promotes cancer cell invasion and migration, indicating a role in tumor development or progression. Functional: The passage describes the effects of the HER2V777L variant on cellular migration and invasion, suggesting that it alters molecular or biochemical functions related to these processes.

      Gene→Variant (gene-first): 2064:V777L

      Genes: 2064

      Variants: V777L

      CIViC paragraph-level PMC10527017 Oncogenic Functional
    26. karim2001khoury 19 Feb 2026
      We previously reported the development of a novel transgenic mouse that conditionally expresses the human HER2 V777L cDNA (abbreviated as "H"), which is inserted into the Rosa26 locus using TALEN-based genome editing. Ou

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage describes the PIK3CA H1047R variant as a gain-of-function allele and activating mutation commonly found in human breast cancers, indicating its role in tumor development or progression.

      Gene→Variant (gene-first): 5290:H1047R 2064:V777L

      Genes: 5290 2064

      Variants: H1047R V777L

      CIViC paragraph-level PMC10527017 Oncogenic
    27. karim2001khoury 19 Feb 2026
      Tumor formation in mice with HER2V777L and PIK3CAH1047R

      [Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 2

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage indicates that the HER2V777L variant is involved in tumor formation in mice, suggesting it contributes to tumor development or progression.

      Gene→Variant (gene-first): 2064:V777L

      Genes: 2064

      Variants: V777L

      CIViC paragraph-level PMC10527017 Oncogenic
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    pmc.ncbi.nlm.nih.gov/articles/PMC10527017/pdf/nihms-1907887.pdf