(P 416) THE PROTEOGENOMIC SUBTYPING OF OSTEOSARCOMA

Location: The Liffey, Level 1

Author(s)

Yingqi Hua

Professor
Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Shanghai, Shanghai, China (People's Republic)

Co-Author(s)

Yafei Jiang

85 Wujin Road. Shanghai, China.
Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Shanghai, Shanghai, China (People's Republic)
QD

Qun Dong, n/a

Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
Shanghai, Shanghai, China (People's Republic)
BH

Binbin Hao, n/a

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Shanghai, Shanghai, China (People's Republic)
Lei Zhao, PhD

postdoctor
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Shanghai, Shanghai, China (People's Republic)
JL

Jing Li, n/a

Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
Shanghai, Shanghai, China (People's Republic)
MT

Minjia Tan, n/a

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Shanghai, Shanghai, China (People's Republic)

Objective: Osteosarcoma (OS) is a prevalent malignant bone tumor that predominantly affects pediatric, adolescent, and young adult populations. Despite the significant advancements in neoadjuvant chemotherapy and surgical techniques, which have resulted in a remarkable improvement in overall survival rates to approximately 70%, there has been minimal progress in achieving substantial enhancements in the 5-year survival rates over the past four decades. Previously, we published a molecular subtyping of OS based on genomic and transcriptomic data (Nat Commun. 2022 Nov 23;13(1):7207.). However, proteomics has long been seen as a promising technique complementary to genomics for elucidating cancer biology and identifying diagnostic and predictive biomarkers.

Methods: We conducted a comprehensive proteogenomic analysis of primary OS samples derived from a cohort of 154 patients. The aim of this study was to define distinct subgroups based on proteomic profiling and evaluate their correlation with key clinical and molecular characteristics, including patient survival, tumor metastasis, chemosensitivity, and genomic profiles.

Results: The proteomic subgroups identified in this study displayed distinct molecular features related to metabolic reprogramming, microenvironment dysregulation, cell proliferation, and potential therapeutic targets. Subgroup 1, denoted as the immune subgroup (S-Im), exhibited the highest expression levels of immune, inflammatory, and stromal proteins. Subgroup 2, denoted as the metabolism dysregulated subgroup (S-Me), exhibited intermediate expression levels of immune and proliferative proteins and showed predominant upregulation of myogenesis, fatty acid metabolism, and oxidative phosphorylation signatures. Subgroup 3, denoted as the proliferation subgroup (S-Pf), showed an increase in proliferative proteins and glycolytic activity. P4HA1, high expression specific to the S-Pf subtype, exerts inhibitory effects on the immune system while simultaneously enhancing metabolic processes. It emerges as a promising therapeutic target for the treatment of the S-Pf subtype.

Conclusion: Our comprehensive and integrated characterization of OS provides a valuable resource that enhances our understanding of the disease. These findings have the potential to guide future clinical strategies for the precise and targeted treatment of OS, ultimately improving patient outcomes.