Integrated mutational landscape analysis of endometrial stromal sarcoma

Area of Science:

• Genomics
• Oncology
• Molecular Biology

Background:

• Endometrial stromal sarcoma (ESS) is a rare uterine malignancy with limited therapeutic strategies.
• Understanding the molecular underpinnings of ESS is crucial for developing effective treatments.

Purpose of the Study:

• To comprehensively characterize the genetic landscape of endometrial stromal sarcoma (ESS) through integrated genomic and transcriptomic sequencing.
• To identify distinct molecular drivers and therapeutic vulnerabilities in low-grade (LG-ESS) and high-grade (HG-ESS) subtypes.

Main Methods:

• Integrated whole-genome, whole-exome, and transcriptome sequencing of 80 ESS tumors (32 LG-ESS, 48 HG-ESS).
• Analysis of mutation burden, copy number alterations, gene fusions, and pathway dysregulation.
• Xenograft model studies for targeted therapy evaluation.

Main Results:

• Identified RAD54B amplification as an oncogenic driver in 18.8% of ESS tumors, correlating with shorter survival.
• Discovered distinct genetic profiles: HG-ESS frequently mutated tumor suppressors (PTEN, TP53) and lost cell-cycle regulators, while LG-ESS featured canonical fusions (e.g., JAZF1-SUZ12) and metabolic gene deletions.
• Six hypermutated ESS cases (7.5%) with POLE or mismatch repair mutations suggest potential immunotherapy response.
• Demonstrated significant tumor suppression and survival extension in an NRAS-mutant xenograft using combined MEK and FAK inhibition.

Conclusions:

• This comprehensive genomic analysis defines the molecular heterogeneity of ESS, differentiating between LG-ESS and HG-ESS.
• RAD54B amplification is a novel oncogenic driver in ESS, and specific molecular alterations point to distinct therapeutic vulnerabilities.
• The findings provide a strong preclinical foundation for developing precision therapies, including immunotherapy and targeted agents, for ESS patients.