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Updated: Jun 16, 2026

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
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Comprehensive molecular profiling of FH-deficient renal cell carcinoma identifies molecular subtypes and potential

Xingming Zhang1, Junjie Zhao1, Xiaoxue Yin2

  • 1Department of Urology, Institute of Urology, Sichuan Clinical Research Center for kidney and urologic diseases, West China Hospital, Sichuan University, Chengdu, China.

Nature Communications
|May 12, 2025
PubMed

Insights

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is aggressive. Integrated genomic study identifies three subtypes with distinct therapeutic responses, guiding precision medicine for this lethal kidney cancer.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) represents a rare and highly lethal subtype of kidney cancer.
  • Understanding its molecular underpinnings is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To conduct a comprehensive integrated genomic study of FH-deficient RCC.
  • To identify molecular subtypes and their association with tumor heterogeneity and methylation patterns.
  • To predict treatment responses based on molecular characteristics.

Main Methods:

  • Integrated genomic analysis of FH-deficient RCC.
  • Development of a CpG site-specific methylation signature for FH-deficient RCC identification.
  • Transcriptomic analysis to define molecular subtypes based on pathway enrichment.

Main Results:

  • Three distinct molecular subtypes (C1, C2, C3) were identified based on pathway enrichment (immune/angiogenic/stromal, WNT/Notch/MAPK, proliferation/stemness).
  • Subtype C1 showed significant survival benefit from combined immune checkpoint blockade (ICB) and anti-angiogenic therapy.
  • Subtypes C2 and C3 exhibited varying responses to these therapies, with C3 showing an unfavorable outcome to anti-angiogenic monotherapy and combination with ICB.

Conclusions:

  • FH-deficient RCC exhibits significant molecular heterogeneity.
  • Distinct subtypes correlate with differential responses to immunotherapy and anti-angiogenic treatments.
  • These findings provide a foundation for precision medicine approaches in managing FH-deficient RCC.

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