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Succinate Dehydrogenase B (SDHB) Overexpression with Enzymatic Dysfunction Defines a Distinct Subtype of Undifferentiated Pleomorphic Sarcoma

2025-10-01Artigo científico Acesso aberto
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dc.contributor.authorEsperança-Martins, Miguel
dc.contributor.authorVasques, Hugo
dc.contributor.authorRavasqueira, Manuel Sokolov
dc.contributor.authorSantos, Filipa
dc.contributor.authorFonseca, Filipa
dc.contributor.authorQueiroz, António Syder
dc.contributor.authorBoavida, João
dc.contributor.authorJordão, Daniel Martins
dc.contributor.authorSoares do Brito, Joaquim
dc.contributor.authorCorredeira, Patrícia
dc.contributor.authorMartins, Marta
dc.contributor.authorAfonso, Ângela
dc.contributor.authorLópez, Jorge Antonio
dc.contributor.authorHuang, Richard S.P.
dc.contributor.authorMelo-Alvim, Cecília
dc.contributor.authorFernandes, Isabel
dc.contributor.authorLópez-Presa, Dolores
dc.contributor.authorLemos, Maria Manuel
dc.contributor.authorVan Tine, Brian A.
dc.contributor.authorBastos, Alliny C.S.
dc.contributor.authorCasimiro, Sandra
dc.contributor.authorAbecasis, Nuno
dc.contributor.authorCosta, Luís
dc.contributor.authorGonçalves, Emanuel
dc.contributor.authorDuarte, Iola F.
dc.contributor.authorDias, Sérgio
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.pblAACR - American Association for Cancer Research
dc.date.accessioned2025-11-19T21:10:40Z
dc.date.available2025-11-19T21:10:40Z
dc.date.issued2025-10-01
dc.descriptionPublisher Copyright: ©2025 The Authors; Published by the American Association for Cancer Research.
dc.description.abstractUndifferentiated pleomorphic sarcoma (UPS) remains one of the most clinically aggressive and poorly characterized soft-tissue sarcoma subtypes. To uncover distinctive molecular traits for UPS, a multiomics analysis of UPS compared with leiomyosarcoma (LMS) and liposarcoma (LPS) was performed. Transcriptomic profiling revealed that UPS exhibits overexpression of genes encoding succinate dehydrogenase (SDH) subunits, particularly SDHB, SDHC, and SDHD, distinguishing it from LMS and dedifferentiated LPS. This finding was validated using The Cancer Genome Atlas Sarcoma dataset. High SDHB expression in UPS was significantly associated with shorter overall survival, shorter recurrence-free survival, and shorter overall survival from the date of first metastasis. IHC validated elevated SDHB protein levels in UPS and LMS relative to dedifferentiated LPS. Despite overexpression of SDH subunits, metabolomic profiling demonstrated a significantly higher succinate-to-fumarate ratio in UPS, suggesting functional impairment of SDH enzymatic activity potentially due to posttranslational modifications, altered assembly of SDH subunits, or imbalanced tricarboxylic acid flux. This paradoxical phenotype of SDH overexpression with enzymatic dysfunction defines a unique molecular and metabolic subtype of UPS with prognostic significance. Recognition of this distinct SDH-associated molecular and metabolic phenotype provides insights into UPS pathogenesis, identifies a potential novel prognostic biomarker, and suggests a new avenue for metabolic-targeted therapy. SIGNIFICANCE: This study identified a paradoxical phenotype of SDH subunit overexpression with functional impairment in UPS, defining a molecular/metabolic subtype associated with poor prognosis. It offers new data on UPS pathogenesis and treatment.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent12
dc.format.extent25480361
dc.identifier.doi10.1158/2767-9764.CRC-25-0468
dc.identifier.issn2767-9764
dc.identifier.otherPURE: 135053290
dc.identifier.otherPURE UUID: 4bdb1186-d7e0-4c98-a8ac-281866fb48c4
dc.identifier.otherScopus: 105020619564
dc.identifier.otherPubMed: 41081835
dc.identifier.urihttp://hdl.handle.net/10362/191086
dc.identifier.urlhttps://www.scopus.com/pages/publications/105020619564
dc.language.isoeng
dc.peerreviewedyes
dc.subjectOncology
dc.subjectCancer Research
dc.subjectSDG 3 - Good Health and Well-being
dc.titleSuccinate Dehydrogenase B (SDHB) Overexpression with Enzymatic Dysfunction Defines a Distinct Subtype of Undifferentiated Pleomorphic Sarcomaen
dc.typejournal article
degois.publication.firstPage1934
degois.publication.issue10
degois.publication.lastPage1945
degois.publication.titleCancer research communications
degois.publication.volume5
dspace.entity.typePublication
rcaap.rightsopenAccess

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