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María Santos1, Javier Lanillos1, Eduardo Caleiras2

  • 1Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO) Madrid 28029, Spain.

American Journal of Cancer Research
|June 9, 2023
PubMed
Summary

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Prognostic and Predictive Value of the Clearseq1-4 Tumor Microenvironment Classification in Localized and Metastatic Clear-Cell Renal Cell Carcinoma.

Cancer research communications·2026
This summary is machine-generated.

Somatic mutations in PBRM1 and KDM5C genes are common in clear cell renal cell carcinoma (ccRCC). These mutations cooperate to increase tumor angiogenesis and enhance the benefit of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor (VEGFR-TKI) therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors (VEGFR-TKIs) are standard antiangiogenic treatments for renal cancer.
  • While Von Hippel-Lindau (VHL) dysfunction predicts sensitivity to VEGFR-TKIs, the impact of mutations in chromatin remodelers Polybromo-1 (PBRM1) and Lysine Demethylase 5C (KDM5C) is not well understood.

Purpose of the Study:

  • To investigate the role of individual and concurrent mutations in PBRM1 and KDM5C on tumor angiogenesis and response to VEGFR-TKIs in clear cell renal cell carcinoma (ccRCC).
  • To analyze the association between PBRM1 and KDM5C mutations and patient outcomes in ccRCC treated with VEGFR-TKIs.

Main Methods:

  • Analysis of tumor mutational and expression profiles from 155 unselected ccRCC cases treated with first-line VEGFR-TKIs.
Keywords:
Clear cell renal cell carcinomaKDM5CPBRM1antiangiogenic responseconcurrent mutationstumor angiogenesis

Related Experiment Videos

  • Validation of findings using ccRCC cases from the IMmotion151 trial.
  • Assessment of tumor angiogenesis, best response to VEGFR-TKIs, and progression-free survival (PFS) in relation to PBRM1 and KDM5C mutation status.

    • Main Results:

    • Concurrent PBRM1 and KDM5C (PBRM1&KDM5C) mutations were found in 4-9% of ccRCC cases and were enriched in favorable-risk patients.
    • PBRM1 or PBRM1&KDM5C mutations were associated with increased tumor angiogenesis. Tumors with only KDM5C mutations showed a similar trend.
    • Best response to VEGFR-TKIs was observed in PBRM1&KDM5C mutated cases, followed by KDM5C-only or PBRM1-only mutated cases. A trend for longer PFS was noted in PBRM1-only mutated cases.
    • Validation confirmed increased angiogenesis and longest PFS in the VEGFR-TKI arm for PBRM1&KDM5C mutated cases, intermediate for single mutations, and shortest for non-mutated cases.

    Conclusions:

    • Somatic PBRM1 and KDM5C mutations are common in metastatic ccRCC.
    • These mutations likely cooperate to increase tumor angiogenesis.
    • PBRM1 and KDM5C mutations are associated with improved benefit from VEGFR-TKI-based antiangiogenic therapy in ccRCC.