Succinate Dehydrogenase B (SDHB) Overexpression with Enzymatic Dysfunction Defines a Distinct Subtype of Undifferentiated Pleomorphic Sarcoma
Year: 2025
Type: article
Study design: Observational Study
Abstract: Undifferentiated 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.
Source: Cancer Research Communications
Authors: Miguel Esperança-Martins, Hugo Vasques, Manuel Sokolov Ravasqueira, Filipa Santos, Filipa Fonseca, António Syder Queiroz, João Boavida, Daniel Martins Jordão, Joaquim Soares do Brito, Patrícia Corredeira, Marta Martins, Ângela Afonso, Jorge Antonio López, Richard S.P.Huang, Cecília Melo Alvim, Isabel Fernandes, Dolores López Presa, Maria Manuel Lemos, Brian A. Van Tine, Alliny Bastos, Sandra Casimiro, Nuno Abecasis, Luís Costa, Emanuel Gonçalves, Iola Duarte, Sérgio Dias
Institutions: University of Lisbon, Gulbenkian Institute for Molecular Medicine, Unidade Local de Saúde Santa Maria, Instituto Português de Oncologia Francisco Gentil, Instituto de Engenharia de Sistemas e Computadores Investigação e Desenvolvimento, Instituto Superior Técnico, Instituto de Medicina Molecular João Lobo Antunes, F. Hoffmann-La Roche AG, Foundation Medicine (United States), Hospital CUF Descobertas, Comprehensive Health Research Centre, Universidade Nova de Lisboa, St. Louis Children's Hospital, Washington University in St. Louis, Alvin J. Siteman Cancer Center, Centro Académico de Medicina de Lisboa, IST-ID - Associação do Instituto Superior Técnico para a Investigação e Desenvolvimento, University of Aveiro
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,550
Funders: Amgen, Eli Lilly and Company, Pfizer, AstraZeneca, Roche, Gilead Sciences, Astellas Pharma, Ministério da Ciência, Tecnologia e Ensino Superior, Servier, PharmaMar, Rede de Química e Tecnologia, Laboratório Associado para a Química Verde, Centro de Investigação em Materiais Cerâmicos e Compósitos, Foundation Medicine, Fundação para a Ciência e a Tecnologia
OpenAlex ID: W4415129083