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Transcriptomic Stratification Reveals an FRS2-Associated, Proliferation-Independent Phenotype in MDM2-High Sarcomas

Takao Sakai1, Hisaki Aiba1, Makoto Yamaguchi1

  • 1Department of Orthopaedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.

Current Oncology (Toronto, Ont.)
|July 27, 2026
PubMed

Insights

Murine Double Minute 2 (MDM2) amplification in sarcomas impacts prognosis. MDM2 expression combined with the Complexity Index in SARComas (CINSARC) signature refines metastasis risk assessment, identifying fibroblast growth factor receptor substrate 2 (FRS2) as a potential marker of aggressive behavior.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • Sarcomas with Murine Double Minute 2 (MDM2) amplification are targets for MDM2-inhibitor therapy.
  • Limited efficacy of MDM2 inhibitor monotherapy indicates other factors influence sarcoma behavior.

Purpose of the Study:

  • To investigate the relationship between MDM2 expression and the Complexity Index in SARComas (CINSARC) transcriptomic signature.
  • To assess the prognostic value of MDM2 and CINSARC in soft tissue sarcomas.
  • To explore potential markers of aggressive behavior independent of proliferation.

Main Methods:

  • Analysis of the public GSE21050 dataset (310 soft tissue sarcomas).
  • Correlation analysis between MDM2 expression, CINSARC signature, and metastasis-free survival.
  • Investigation of gene expression in the 12q13-15 region, focusing on fibroblast growth factor receptor substrate 2 (FRS2).

Main Results:

  • The MDM2-low/CINSARC-low subgroup exhibited the most favorable metastasis-free survival.
  • The MDM2-high/CINSARC-low subgroup showed unfavorable metastasis-free survival, similar to the MDM2-high/CINSARC-high group.
  • Fibroblast growth factor receptor substrate 2 (FRS2) expression positively correlated with MDM2 but not CINSARC, suggesting an association independent of proliferation.

Conclusions:

  • Proliferation-based risk assessment may underestimate metastatic risk in some MDM2-high sarcomas.
  • FRS2 may serve as a biologically relevant marker for aggressive sarcoma behavior, independent of tumor proliferation.
  • Combined MDM2 and CINSARC analysis offers a more refined prognostic stratification for soft tissue sarcomas.
Keywords:
12q13-15 ampliconCINSARCFRS2MDM2metastasis-free survivalsoft tissue sarcomatranscriptomic analysis

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