| Sumario: | Simple Summary: Sarcomas with murine double minute 2 (MDM2) amplification are promising candidates for targeted therapy. However, their treatment response remains limited. To further investigate this limitation, we analyzed a publicly available dataset of 310 soft tissue sarcomas and examined the relationship between MDM2 expression and the Complexity Index in the SARComas (CINSARC) transcriptomic signature, a gene expression signature that reflects cell division and chromosomal instability. We found that a subset of tumors with high MDM2 expression had a low proliferative profile (CINSARC-low), but still showed poor metastasis-free survival. Additionally, fibroblast growth factor receptor substrate 2 (FRS2), a gene located near MDM2, was strongly coexpressed with MDM2 and showed no clear association with CINSARC. These findings suggest that proliferation-based risk assessment alone may underestimate the metastatic risk of a subset of MDM2-high sarcomas, and FRS2 may present a biologically relevant marker associated with aggressive behavior independent of tumor proliferation. Sarcomas with Murine Double Minute 2 (MDM2) amplification are considered potential candidates for MDM2-targeted therapy. However, the limited efficacy of MDM2 inhibitor monotherapy suggests that additional biological factors may influence tumor behavior and prognosis. This study investigated the relationship between MDM2 expression and the Complexity Index in SARComas (CINSARC) transcriptomic signature, a gene expression signature that reflects cell division and chromosomal instability in soft tissue sarcomas. In the public GSE21050 dataset comprising 310 soft tissue sarcomas, the MDM2-low/CINSARC-low subgroup showed the most favorable metastasis-free survival, whereas the MDM2-high/CINSARC-low subgroup had an unfavorable metastasis-free survival comparable to that of the MDM2-high/CINSARC-high group. Among the representative genes in the 12q13-15 region, fibroblast growth factor receptor substrate 2 (FRS2) showed a strong positive correlation with MDM2 expression, but no significant correlation with CINSARC, suggesting an association independent of proliferative capacity. These findings suggest that proliferation-based risk assessment alone may underestimate the metastatic risk of a subset of MDM2-high sarcomas, and FRS2 may present a biologically relevant marker of aggressive behavior independent of tumor proliferation.
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