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Comparative Lesions Analysis Through a Targeted Sequencing Approach

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Large-Scale Multiomic Analysis Identifies Anatomic Differences and Immunogenic Potential in Subtypes of

Galina Lagos¹, Roman Groisberg², Andrew Elliott³

¹Brown University, Providence, RI, United States.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

|March 18, 2025

Summary

Uterine leiomyosarcomas (uLMS) are molecularly distinct from other subtypes. Non-uterine LMS show more immune activity, suggesting potential for immunotherapy in specific leiomyosarcoma (LMS) cases.

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Area of Science:

Oncology
Genomics
Immunology

Background:

Leiomyosarcomas (LMS) are rare soft tissue sarcomas with poorly characterized genomic and immune profiles.
Anatomic subtypes of LMS, such as uterine (uLMS) and non-uterine (retroperitoneal, other), exhibit distinct clinical behaviors.

Purpose of the Study:

To define the genomic and immune landscapes of LMS by anatomic subtypes.
To compare these profiles across subtypes and with melanoma.
To infer real-world outcomes of immune checkpoint inhibitors (ICI) in LMS.

Main Methods:

Comprehensive DNA/RNA sequencing of 1,115 LMS samples (uLMS, retroperitoneal LMS, oLMS).
Comparison of genomic/transcriptomic profiles across subtypes.
Immune profiling compared to melanoma (n=1,255).
Analysis of insurance claims data for real-world ICI outcomes.

Main Results:

Uterine LMS (uLMS) were molecularly distinct from non-uLMS, with specific mutations (MED12 in uLMS; RB1, MAP2K4 in non-uLMS).
Non-uLMS showed upregulated immune gene sets and higher immune cell infiltration (CD8+ T cells, B cells) compared to uLMS.
LMS had lower immune cell abundance and T cell-inflamed scores (TIS) than melanoma, but 11% of oLMS had high TIS.
In real-world data, 29% of LMS patients on ICI showed potential benefit (>6 months treatment).

Conclusions:

Uterine LMS (uLMS) is a molecularly distinct entity from non-uLMS.
uLMS are characterized by an 'immune cold' phenotype compared to non-uLMS.
Despite similar traditional biomarkers, immune signals in some LMS suggest potential for immunotherapy, warranting further research.