Uterine adenosarcomas are mesenchymal neoplasms

Area of Science:

• Gynecologic Pathology
• Cancer Genomics
• Molecular Oncology

Background:

• Uterine adenosarcomas (UAs) are biphasic tumors with malignant mesenchymal (stromal) and benign epithelial components.
• While generally low-grade, sarcomatous overgrowth indicates a poorer prognosis.
• The cellular origin and genetic landscape of UAs remain incompletely understood.

Purpose of the Study:

• To investigate the somatic genetic alterations in uterine adenosarcomas.
• To determine if genetic alterations are restricted to the mesenchymal component, as hypothesized.
• To clarify the clonal relationship between the epithelial and mesenchymal components.

Main Methods:

• Whole-exome sequencing, targeted capture sequencing, and RNA sequencing were performed on 20 UAs.
• Laser-capture microdissection and in situ hybridization were used to localize genetic alterations.
• Mitochondrial DNA sequencing analyzed the clonal relationship between components.

Main Results:

• Recurrent mutations were rare, affecting FGFR2, KMT2C, and DICER1.
• Gene amplifications (MDM2/CDK4/HMGA2, TERT) and NCOA fusions were identified.
• All detected somatic genetic alterations were confined to the mesenchymal component.
• Epithelial and mesenchymal components were found to be clonally unrelated.

Conclusions:

• Uterine adenosarcomas are mesenchymal neoplasms with genetic alterations restricted to the stromal component.
• The study provides evidence for the clonal independence of the epithelial and mesenchymal elements.
• These findings advance the understanding of UA pathogenesis and classification.