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Proteogenomic profiling of soft tissue leiomyosarcoma reveals distinct molecular subtypes with divergent outcomes and
Atsushi Tanaka1,2,3, Makiko Ogawa1,3, Yusuke Otani1
1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Abstract:
Soft tissue leiomyosarcoma (STLMS) is an aggressive malignancy lacking validated molecular subclassification and effective targeted treatments. We performed comprehensive proteogenomic analysis of primary and metastatic STLMS to uncover biological traits and therapeutic weaknesses. Integrative proteomic and phosphoproteomic analyses using non-negative matrix factorization identified three subtypes. Subtype P1 shows genomic stability, low proliferation, and enrichment of FGFR2 and PDK signaling pathways. Subtype P2 exhibits chromosomal instability, inflammatory programs, activation of CDK-AURKA/B-mTOR/ERK kinome with IGF1R/PDGFRA gene alterations, and poorest survival outcomes. Subtype P3 is highly proliferative, with E2F/DNA-repair programs, elevated NCOR1, and shift towards nonhomologous end joining with upregulation of PARP1. Homologous recombination deficiency (HRD) analysis distinguishes HRD-low P1 from HRD-high P2/P3. Paired analyses suggest HRD increases in metastases within P3. Immune profiling shows P2 as immunosuppressive, characterized by LGALS9 and M2 macrophages. Our proteogenomic analyses provide a molecular landscape of LMS, revealing biological insights, patient outcome stratification, and therapeutic targets.
Insights
Soft tissue leiomyosarcoma (STLMS) subtypes were identified through proteogenomic analysis, revealing distinct molecular profiles and potential therapeutic targets for this aggressive cancer. These findings stratify patients and highlight weaknesses for future treatment development.
Area of Science:
- Oncology
- Genomics
- Proteomics
Background:
- Soft tissue leiomyosarcoma (STLMS) is an aggressive malignancy.
- STLMS lacks validated molecular subclassification and effective targeted treatments.
Purpose of the Study:
- To perform comprehensive proteogenomic analysis of STLMS.
- To uncover biological traits and therapeutic weaknesses of STLMS.
Main Methods:
- Integrative proteomic and phosphoproteomic analyses using non-negative matrix factorization.
- Homologous recombination deficiency (HRD) analysis.
- Immune profiling.
Main Results:
- Identified three STLMS subtypes (P1, P2, P3) with distinct genomic, proliferative, and signaling pathway characteristics.
- Subtype P2 showed chromosomal instability, inflammatory programs, and poorest survival.
- Subtype P3 exhibited high proliferation and a shift towards nonhomologous end joining.
- HRD analysis distinguished subtypes, with P3 showing increased HRD in metastases.
- Immune profiling revealed P2 as immunosuppressive.
Conclusions:
- Proteogenomic analysis provides a molecular landscape of STLMS.
- Identified patient outcome stratification based on molecular subtypes.
- Revealed potential therapeutic targets and weaknesses for STLMS treatment.
