A Comprehensive Understanding of the Genomic Bone Tumor Landscape: A Multicenter Prospective Study

Abstract

Complexity and heterogeneity increases the difficulty of diagnosis and treatment of bone tumors. We aimed to identify the mutational characterization and potential biomarkers of bone tumors. In this study, a total of 357 bone tumor patients were recruited and the next generation sequencing (NGS)-based YuanSu450 panel, that includes both DNA and RNA sequencing, was performed for genomic alteration identification. The most common mutated genes in bone tumors included <i>TP53</i>, <i>NCOR1</i>, <i>VEGFA</i>, <i>RB1</i>, <i>CCND3</i>, <i>CDKN2A</i>, <i>GID4, CCNE1</i>, <i>TERT</i>, and <i>MAP2K4</i>. The amplification of genes such as <i>NCOR1</i>, <i>VEGFA</i>, and <i>CCND3</i> mainly occurred in osteosarcoma. Germline mutation analysis reveal a high frequency of HRD related mutations (46.4%, 13/28) in this cohort. With the assistance of RNA sequencing, 16.8% (19/113) gene fusions were independently detected in 20% (16/79) of patients. Nearly 34.2% of patients harbored actionable targeted mutations, of which the most common mutation is <i>CDKN2A</i> deletion. The different mutational characterizations between juvenile patients and adult patients indicated the potential effect of age in bone tumor treatment. According to the genomic alterations, the diagnosis of 26 (7.28%) bone tumors were corrected. The most easily misdiagnosed bone tumor included malignant giant cell tumors of bone (2.8%, 10/357) and fibrous dysplasia of bone (1.7%, 6/357). Meanwhile, we found that the mutations of <i>MUC16</i> may be a potential biomarker for the diagnosis of mesenchymal chondrosarcomas. Our results indicated that RNA sequencing effectively complements DNA sequencing and increased the detection rate of gene fusions, supporting that NGS technology can effectively assist the diagnosis of bone tumors.