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Clinically Relevant Molecular Subtypes in Leiomyosarcoma
Xiangqian Guo1, Vickie Y Jo2, Anne M Mills3
1Department of Pathology, Stanford University School of Medicine, Stanford, California.
Purpose:
Leiomyosarcoma is a malignant neoplasm with smooth muscle differentiation. Little is known about its molecular heterogeneity and no targeted therapy currently exists for leiomyosarcoma. Recognition of different molecular subtypes is necessary to evaluate novel therapeutic options. In a previous study on 51 leiomyosarcomas, we identified three molecular subtypes in leiomyosarcoma. The current study was performed to determine whether the existence of these subtypes could be confirmed in independent cohorts.
Experimental Design:
Ninety-nine cases of leiomyosarcoma were expression profiled with 3'end RNA-Sequencing (3SEQ). Consensus clustering was conducted to determine the optimal number of subtypes.
Results:
We identified 3 leiomyosarcoma molecular subtypes and confirmed this finding by analyzing publically available data on 82 leiomyosarcoma from The Cancer Genome Atlas (TCGA). We identified two new formalin-fixed, paraffin-embedded tissue-compatible diagnostic immunohistochemical markers; LMOD1 for subtype I leiomyosarcoma and ARL4C for subtype II leiomyosarcoma. A leiomyosarcoma tissue microarray with known clinical outcome was used to show that subtype I leiomyosarcoma is associated with good outcome in extrauterine leiomyosarcoma while subtype II leiomyosarcoma is associated with poor prognosis in both uterine and extrauterine leiomyosarcoma. The leiomyosarcoma subtypes showed significant differences in expression levels for genes for which novel targeted therapies are being developed, suggesting that leiomyosarcoma subtypes may respond differentially to these targeted therapies.
Conclusions:
We confirm the existence of 3 molecular subtypes in leiomyosarcoma using two independent datasets and show that the different molecular subtypes are associated with distinct clinical outcomes. The findings offer an opportunity for treating leiomyosarcoma in a subtype-specific targeted approach.
Insights
Three molecular subtypes of leiomyosarcoma were confirmed in independent cohorts. These subtypes correlate with distinct clinical outcomes, paving the way for subtype-specific targeted therapies for leiomyosarcoma.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Leiomyosarcoma is a rare smooth muscle cancer with unknown molecular heterogeneity.
- Currently, no targeted therapies exist for leiomyosarcoma, necessitating molecular subtyping for treatment evaluation.
Purpose of the Study:
- To confirm previously identified molecular subtypes of leiomyosarcoma in independent patient cohorts.
- To identify diagnostic markers and assess the clinical relevance of leiomyosarcoma subtypes.
Main Methods:
- Expression profiling of 99 leiomyosarcoma cases using 3'end RNA-Sequencing (3SEQ).
- Consensus clustering to determine molecular subtypes.
- Validation using The Cancer Genome Atlas (TCGA) data and immunohistochemistry.
Main Results:
- Three distinct molecular subtypes of leiomyosarcoma were confirmed across independent datasets.
- Identified LMOD1 and ARL4C as diagnostic markers for subtype I and II leiomyosarcoma, respectively.
- Subtype I associated with good prognosis in extrauterine cases; Subtype II associated with poor prognosis in both uterine and extrauterine leiomyosarcoma.
Conclusions:
- The existence of three molecular subtypes in leiomyosarcoma is confirmed, each linked to specific clinical outcomes.
- These findings support a subtype-specific targeted treatment approach for leiomyosarcoma.
