Abstract 5669: Distinct genetic features between osteosarcomas firstly metastasizing to bone and to lung
Authors: Xie Lu , Cai Zhenyu , Tang Xiaodong , Guo Wei , Meng Fanfei , Zhang Xin , Shi Xiaoliang , Pang Fei 
Published: June 2022

Abstract
Background Osteosarcoma (OS) is a highly aggressive malignant tumor of mesenchymal origin and prone to early hematogenous metastases. The 5-year overall survival of metastatic OS is only approximately 20% to 30%. Therefore, it is still clinical dilemma in the treatment of OS. Thus,understanding the molecular features of metastatic osteosarcoma become increasingly important.
Methods Formalin-fixed, paraffin-embedded or fresh tissues and matched blood samples were collected from OS patients for whole exome sequencing using next-generation sequencing at OrigiMed (Shanghai, China), a College of American Pathologists accredited and Clinical Laboratory Improvement Amendments certified laboratory. Genomic alterations including single nucleotide variations (SNVs), short and long insertions/deletions (INDELs), copy number variations (CNVs), and gene rearrangements were assessed. Tumor mutational burden (TMB) and the number of tumor neoantigens (NEO) were also measured.
Results In total, 38 patients including 29 males and 9 females were recruited with a median age of 19.5 years. Among them, 12 patients had first metastases to bone (group B). The metastatic sites included femur, fibula, pelvis, ribs, sacrum, and spine. The median age of group B was 19.5 years. Twenty-six (26) patients had first metastases to lung (group L). The median age of group L was 14 years.The most frequently mutated genes in OS was TP53 (55.3%), followed by MYC (36.8%), MUC16 (26.3%), PTK2 (21.1%), RAD21 (21.1%), and CDK4 (18.4%). However, genetic features between Groups B and Group L patients were different. In group B patients, the median percentage of SNVs and short INDELs was 94.7% of the overall mutations, and the median percentage of CNVs was 4.3%. In contrast, the median percentage of SNVs and short INDELs in group L was 58.8%, and the median percentage of CNVs was 36.7%. The mutations patterns were clearly different between Group B and Group L with a predominant SNV & INDEL in Group B and a mixture feature of SNV & INDEL and CNV in Group L. Inaddition the median TMB in group B was significantly higher than that in group L (4.85 muts/Mb vs 2.4 muts/Mb, P&lt;0.05). Also, the median number of tumor NEO in group B was nearly 6 times higher than that in group L (743 vs 128.5, P=0.0016).
Conclusion Our study identified different molecular features of patients with OS firstly metastasizing to lung and to bone. OS with first bone metastases had a predominant SNV and short INDEL, high TMB level, and high NEO counts, while OS with first lung metastasis had an increased CNV, low TMB, and low NEO counts. Our results suggest that metastatic OS that firstly spread to bone and to lung may be two distinct subgroups and may adopt different treatment strategies.
Citation Format: Lu Xie, Zhenyu Cai, Xiaodong Tang, Wei Guo, Fanfei Meng, Xin Zhang, Xiaoliang Shi, Fei Pang. Distinct genetic features between osteosarcomas firstly metastasizing to bone and to lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5669.