Lauren J Mills1,2, Logan G Spector1,2,3, David A Largaespada1,2,4,5,6, Lindsay A Williams7,8,9,10. 1. Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, MN, USA. 2. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. 3. Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA. 4. Brain Tumor Program, University of Minnesota, Minneapolis, MN, USA. 5. Department of Genetics, Cell Biology and Development, University of Minnesota School of Medicine, Minneapolis, MN, USA. 6. Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA. 7. Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, MN, USA. lawilliams@umn.edu. 8. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. lawilliams@umn.edu. 9. Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA. lawilliams@umn.edu. 10. Brain Tumor Program, University of Minnesota, Minneapolis, MN, USA. lawilliams@umn.edu.
Abstract
BACKGROUND: Males < 40 years old are more likely to be diagnosed with and die from osteosarcoma (OS). The underlying mechanisms may depend on sex differences in immune response. METHODS: We used SEER data to estimate survival differences between males and females aged < 40 years at OS diagnosis. In NCI TARGET-OS cases, we determined sex differences in gene expression, conducted Gene Set Enrichment Analysis (GSEA), and applied the LM22 signature to identify biologic sex differences. We compared sex differences in gene expression profiles in TARGET-OS to those observed in Sleeping Beauty (SB) transposon mutagenesis accelerated Trp53R270H-mutant mouse-OS and healthy adult osteoblasts. RESULTS: Males had worse 17-year overall survival than females (SEER p < 0.0001). From 87 TARGET-OS cases, we observed 1018 genes and 69 pathways that differed significantly by sex (adjusted p < 0.05). Pathway and gene lists overlapped with those from mice (p = 0.03) and healthy osteoblasts (p = 0.017), respectively. Pathways that differed significantly by sex were largely immune-based and included the PD-1/PD-L1 immunotherapy pathway. We observed sex differences in M2 macrophages (LM22; p = 0.056) and M1-M2 macrophage transition (GSEA; p = 0.037) in TARGET-OS. LM22 trends were similar in mice. Twenty-four genes differentially expressed by sex in TARGET-OS had existing cancer therapies. CONCLUSIONS: Sex differences in OS gene expression were similar across species and centered on immune pathways. Identified sex-specific therapeutic targets may improve outcomes in young individuals with OS.
BACKGROUND: Males < 40 years old are more likely to be diagnosed with and die from osteosarcoma (OS). The underlying mechanisms may depend on sex differences in immune response. METHODS: We used SEER data to estimate survival differences between males and females aged < 40 years at OS diagnosis. In NCI TARGET-OS cases, we determined sex differences in gene expression, conducted Gene Set Enrichment Analysis (GSEA), and applied the LM22 signature to identify biologic sex differences. We compared sex differences in gene expression profiles in TARGET-OS to those observed in Sleeping Beauty (SB) transposon mutagenesis accelerated Trp53R270H-mutant mouse-OS and healthy adult osteoblasts. RESULTS: Males had worse 17-year overall survival than females (SEER p < 0.0001). From 87 TARGET-OS cases, we observed 1018 genes and 69 pathways that differed significantly by sex (adjusted p < 0.05). Pathway and gene lists overlapped with those from mice (p = 0.03) and healthy osteoblasts (p = 0.017), respectively. Pathways that differed significantly by sex were largely immune-based and included the PD-1/PD-L1 immunotherapy pathway. We observed sex differences in M2 macrophages (LM22; p = 0.056) and M1-M2 macrophage transition (GSEA; p = 0.037) in TARGET-OS. LM22 trends were similar in mice. Twenty-four genes differentially expressed by sex in TARGET-OS had existing cancer therapies. CONCLUSIONS: Sex differences in OS gene expression were similar across species and centered on immune pathways. Identified sex-specific therapeutic targets may improve outcomes in young individuals with OS.
Entities:
Keywords:
Gene expression; Mouse osteosarcoma; Osteosarcoma; Pediatric and young adult cancer; Sex differences; Survival disparities
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